HDAC inhibitor

ABSTRACT

A compound having the following formula (I):  
                 
wherein 
     R 1  is hydrogen, lower alkyl, lower alkenyl, lower or higher alkynyl, cyclo(lower)alkyl, cyclo(higher)alkyl, cyclo(lower)alkyl(lower)alkyl, cyclo(higher)alkyl(lower)alkyl, cyclo(lower)alkenyl(lower)alkyl, aryl-fused cyclo(lower)alkyl, lower alkoxy, acyl, aryl, ar(lower)alkoxy, ar(lower)alkyl, heteroar(lower) alkyl, amino, heteroaryl, heterocyclyl or heterocyclyl(lower)alkyl, which may be substituted with one or more suitable substituent(s),    R 2  is hydrogen or lower alkyl, X is arylene, heteroarylene, cycloalkylene, heterocycloalkylene or aryl-fused cycloalkylene, Y is arylene or heteroarylene, which may be substituted with one or more suitable substituent(s), Z is lower alkenylene, which may be substituted with lower alkyl or halogen, or a salt thereof. The compound is useful as a histone deacetylase inhibitor.

TECHNICAL FIELD

The present invention relates to a compound useful as a medicament, andto a pharmaceutical composition comprising the same.

BACKGROUND ART

Histone deacetylase (hereinafter also referred as HDAC) is known to playan essential role in the transcriptional machinery for regulating geneexpression, induce histone hyperacetylation and to affect the geneexpression. Therefore, it is useful as a therapeutic or prophylacticagent for diseases caused by abnormal gene expression such asinflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infections,tumors, etc.

WO 01/38322 discloses an inhibitor of histone deacetylase represented bythe following formula:Cy-L¹-Ar—Y¹—C(O)—NH-Zwherein

-   Cy is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is    optionally substituted;-   L¹ is —(CH₂)_(m)—W— wherein m is an integer of 0 to 4, and W is    selected from the group consisting of —C(O)NH—, —S(O)₂NH—, etc.;-   Ar is optionally substituted arylene, which is optionally fused to    an aryl, heteroaryl ring, etc.;-   Y¹ is a chemical bond or a straight- or branched-chain saturated    alkylene, wherein said alkylene is optionally substituted; and-   Z is selected from the group consisting of anilinyl, pyridyl,    thiadiazolyl and —O-M wherein M is H or a pharmaceutically    acceptable cation.

WO 02/22577 discloses the following hydroxamate compound as adeacetylase inhibitor:

wherein

-   -   R₁ is H, halo or a straight chain C₁-C₆ alkyl;

-   R₂ is selected from H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉    heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, cycloalkylalkyl,    aryl, heteroaryl, etc.;

-   R₃ and R₄ are the same or different and independently H, C₁-C₆    alkyl, acyl or acylamino, or

-   R₃ and R₄ together with the carbon to which they are bound to    represent C═O, C═S, etc., or

-   R₂ together with the nitrogen to which it is bound and R₃ together    with the carbon to which it is bound to form a C₄-C₉    heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic    polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;

-   R₅ is selected from H, C₁-C₆ alkyl, etc.;

-   n, n₁, n₂ and n₃ are the same or different and independently    selected from 0-6, when n₁ is 1-6, each carbon atom can be    optionally and independently substituted with R₃ and/or R₄;

-   X and Y are the same or different and independently selected from H,    halo, C₁-C₄ alkyl, etc.;

-   or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

The present invention relates to a novel compound useful as amedicament, and to a pharmaceutical composition comprising the same.

More particularly, the present invention relates to a compound having apotent inhibitory effect on the activity of histone deacetylase.

The inventors of the present invention have also found that histonedeacetylase inhibitors, such as a compound of the formula (I)(hereinafter compound (I)), have a potent immunosuppressive effect andpotent antitumor effect. Therefore, a histone deacetylase inhibitorssuch as compound (I) is useful as an active ingredient for animmunosuppressant and an antitumor agent, and useful as an activeingredient for a therapeutic or prophylactic agent for diseases such asinflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infections,tumors, etc.

Accordingly, one object of the present invention is to provide acompound having biological activities for treating or preventing thediseases as stated above.

A further object of the present invention is to provide a pharmaceuticalcomposition containing the compound (I) as an active ingredient.

A yet further object of the present invention is to provide use of thehistone deacetylase inhibitors, such as compound (I), for treating andpreventing the diseases as stated above.

A yet further object of the present invention is to provide a commercialpackage comprising the pharmaceutical composition containing thecompound (I) and a written matter associated therewith, the writtenmatter stating that the pharmaceutical composition may or should be usedfor treating or preventing the diseases as stated above.

Thus, the present invention provides A compound having the followingformula (I):

wherein

-   R¹ is hydrogen, lower alkyl, lower alkenyl, lower or higher alkynyl,    cyclo(lower)alkyl, cyclo(higher)alkyl,    cyclo(lower)alkyl(lower)alkyl, cyclo(higher)alkyl(lower)alkyl,    cyclo(lower)alkenyl(lower)alkyl, aryl-fused cyclo(lower)alkyl, lower    alkoxy, acyl, aryl, ar(lower)alkoxy, ar(lower)alkyl,    heteroar(lower)alkyl, amino, heteroaryl, heterocyclyl or    heterocyclyl(lower)alkyl, which may be substituted with one or more    suitable substituent(s),-   R² is hydrogen or lower alkyl,-   X is arylene, heteroarylene, cycloalkylene, heterocycloalkylene or    aryl-fused cycloalkylene,-   Y is arylene or heteroarylene, which may be substituted with one or    more suitable substituent(s),-   Z is lower alkenylene, which may be substituted with lower alkyl or    halogen,-   or a salt thereof.

The above-mentioned compound or a salt thereof can be prepared by theprocesses as illustrated in the following reaction schemes or by themethods disclosed in the Preparations and Examples.

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

wherein

-   R¹, R², X, Y and Z are as defined above,-   Hal is halogen,-   E is protected carboxy or protected carboxy(lower)alkyl,-   F is hydroxy(lower)alkyl,-   G is formyl or formyl(lower)alkyl,-   R³ is hydroxy protecting group,-   R⁴ is protected carboxy,-   J is a single bond or lower alkylene,-   R⁵ and P is amino protecting group,-   Xa is divalent saturated 3 to 8-membered heteromonocyclic ring    containing one nitrogen atom,-   R¹a is cyclo(lower)alkyl or lower alkyl substituted with    cyclo(lower)alkyl,-   R⁶ is cyclo(lower)alkylidene or cyclo(lower)alkylene, and-   R⁷ is hydrogen,-   R⁸ is formyl(lower)alkyl, or-   R⁷ and R⁸ are taken together to form oxo,-   R⁹ is lower alkyl.

In the above-mentioned Processes A, B, C, D, E, F, G, H, I, J, K, L, M,N and O, each of the starting compounds can be prepared, for example,according to the procedures as illustrated in Preparations in thepresent specification or in a manner similar thereto.

The compound (I) of the present invention is obtained from compound[I-2], for example, according to the following processes or methodsdisclosed in the Examples.

wherein

-   R¹, R², R³, X, Y, P and Z are as defined above.    Process 1

The compound (I) is obtained by subjecting the compound (F-2) to theelimination reaction of hydroxy protecting group in the presence of anacid.

The acid includes such as hydrogen chloride solution (e.g. hydrogenchloride in solvent such as methanol, dioxane, ethyl acetate, diethylether, etc.), acetic acid, p-toluenesulfonic acid, boric acid, etc.

Optionally, one or more suitable solvent(s) for the deprotection is(are)used. Such solvent includes such as methanol, ethanol, ethyl acetate,dioxane, diethyl ether, acetic acid, etc.

The temperature of the reaction is not critical, and the reaction isusually carried out from under cooling to heating.

The compound (I) may be a salt, which is also encompassed in the scopeof the present invention. For example, when a basic group such as anamino group is present in a molecule, the salt is exemplified by an acidaddition salt (e.g. salt with an inorganic acid such as hydrochloricacid, hydrobromic acid, sulfuric acid, etc., salt with an organic acidsuch as methanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonicacid, camphorsulfonic acid (e.g.,[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acidor an enantiomer thereof, etc.), fumaric acid, maleic acid, mandelicacid, citric acid, salicylic acid, malonic acid, glutaric acid, succinicacid, etc.), etc., and when an acidic group such as carboxyl group ispresent, the salt is exemplified by a basic salt (e.g. salt with a metalsuch as lithium, sodium, potassium, calcium, magnesium, aluminium, etc.,a salt with amino acid such as lysine, etc.), etc.

In addition, solvates (e.g. hydrate, ethanolate, etc.), anhydrous formsand other polymorphic forms or pharmaceutically acceptable salts of thecompound (I) are also encompassed in the scope of the present invention.

When the compound (I) has stereoisomers based on asymmetric carbonatom(s) or double bond(s), such as an optically active form, a geometricisomer and the like, such isomers and mixtures thereof are alsoencompassed in the scope of the present invention.

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

Each of the terms “halogen”, “halo” and “Hal” may include fluorine,chlorine, bromine and iodine.

The term “lower” used in the description is intended to mean 1 to 6carbon atom(s) unless otherwise indicated.

The term “higher” used in the description is intended to mean 7 to 11carbon atom(s) unless otherwise indicated.

Suitable “one or more” may include the number of 1 to 6, preferably 1 to3.

Suitable “lower alkyl” and “lower alkyl” moiety may include straight orbranched alkyl having 1 to 6 carbon atom(s) such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,tert-pentyl, neopentyl, hexyl, isohexyl, etc.

Suitable “lower alkenyl” and “lower alkenyl” moiety may include straightor branched alkenyl having 2 to 6 carbon atom(s) such as vinyl, allyl,isopropenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, etc.

Suitable “lower alkynyl” and “lower alkynyl” moiety may include straightor branched alkynyl having 2 to 6 carbon atom(s) such as ethynyl,propargyl, 3-methyl-1-pentynyl, etc.

Suitable “higher alkynyl” and “heigher alkynyl” moiety may includestraight or branched alkynyl having 7 to 11 carbon atom(s) such asheptynyl, octynyl, etc.

Suitable “cyclo(lower)alkyl” and “cyclo(lower)alkyl” moiety may includecycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.

Suitable “cyclo(higher)alkyl” and “cyclo(higher)alkyl” moiety mayinclude cycloalkyl having 7 to 11 carbon atoms such as cycloheptyl,cyclooctyl, adamantyl, etc.

Suitable “cyclo(lower)alkenyl” and “cyclo(lower)alkenyl” moiety mayinclude cycloalkenyl having 3 to 6 carbon atoms such as cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

Suitable “aryl-fused cyclo(lower)alkyl” and “aryl-fusedcyclo(lower)alkyl” moiety may include aryl-fused cycloalkyl having 8 to12 carbon atoms such as tetrahydronaphthyl, indanyl, benzocyclobutanyl,etc.

Suitable “lower alkoxy” and “lower alkoxy” moiety may include straightor branched alkoxy having 1 to 6 carbon atom(s) such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc.

Suitable “halo(lower)alkyl” may include lower alkyl substituted with 1to 3 halogen atom(s) such as monochloromethyl, dichloromethyl,trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl,monobromomethyl, dibromomethyl, tribromomethyl, monochloroethyl,dichloroethyl, trichloroethyl, monofluoroethyl, difluoroethyl,trifluoroethyl, etc.

Suitable “halo(lower)alkoxy” may include lower alkoxy substituted with 1to 3 halogen atom(s) such as monochloromethoxy, dichloromethoxy,trichloromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,monobromomethoxy, dibromomethoxy, tribromomethoxy, monochloroethoxy,dichloroethoxy, trichloroethoxy, monofluoroethoxy, difluoroethoxy,trifluoroethoxy, etc.

Suitable “lower alkenylene” may include straight or branched alkenylenehaving 2 to 6 carbon atom(s) such as vinylene, 1-methylvinylene,2-methylvinylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene,2-methyl-2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene,1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene,1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene,etc. Suitable lower alkenylene for Z may be, for example, vinylene,1-methylvinylene, 2-methylvinylene, etc.

Suitable “aryl” or “aryl” moiety described below may include C₆-C₁₆ arylsuch as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, azulenyl, etc.,and this “aryl” or “aryl” moiety described below may be substituted withone or more substituent(s) selected from the group consisting of loweralkyl, halogen, lower alkoxy, amino, hydroxy, cyano, aryl, aryloxy,acyl, cyclo(lower)alkyl, heteroaryl, halo(lower)alkyl orhalo(lower)alkoxy.

Suitable “aryloxy” may include C₆-C₁₆ aryloxy such as phenoxy,naphthyloxy, anthryloxy, pyrenyloxy, phenanthryloxy, azulenyloxy, etc.

Suitable “ar(lower)alkyl” may include phenyl(C₁-C₆)alkyl such as benzyl,phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, etc.,naphthyl(C₁-C₆)alkyl such as naphthylmethyl, naphthylethyl,naphthylpropyl, naphthylbutyl, naphthylpentyl, naphtylhexyl, etc.

Suitable “ar(lower)alkoxy” may include phenyl(C₁-C₆)alkoxy such asbenzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylhexyloxy,etc., naphthyl(C₁-C₆)alkoxy such as naphthylmethoxy, naphthylethoxy,naphthylpropoxy, naphthylbutoxy, naphthylpentyloxy, naphtylhexyloxy,etc.

The “acyl” as used herein includes for example, alkanoyl [e.g., formyl,lower alkyl-carbonyl (e.g., acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, pivaloyl, 2,2-dimethylpropanoyl, hexanoyland the like), heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl,dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl,heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl and the like];

-   alkoxycarbonyl [e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl,    ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,    t-butoxycarbonyl, pentyloxycarbonyl and the like) and the like];-   lower alkyl-carbonyloxy(lower)alkylcarbonyl (e.g. acetyloxyacetyl,    ethylcarbonyloxyacetyl and the like);-   arylcarbonyl [e.g., C₆₋₁₀ arylcarbonyl (e.g., benzoyl, toluoyl,    naphthoyl, fluorenylcarbonyl and the like)];-   arylalkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl,    phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,    phenylhexanoyl and the like), naphthyl(lower)alkanoyl (e.g.,    naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl and the like)    and the like);-   arylalkenoyl [e.g., aryl(C₃-C₆) alkenoyl (e.g., phenylpropenoyl,    phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl    and the like) and the like)];-   naphthylalkenoyl [e.g., naphthyl(C₃-C₆)alkenoyl (e.g.,    naphthylpropenoyl, naphthylbutenoyl, naphthylmethacryloyl,    naphthylpentenoyl, naphthylhexenoyl and the like) and the like];-   arylalkoxycarbonyl [e.g., aryl(lower)alkoxycarbonyl such as    phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl and the like),    fluorenyl(lower)alkoxycarbonyl (e.g., fluorenylmethyloxycarbonyl and    the like) and the like];-   aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl and the    like);-   aryloxyalkanoyl [e.g., aryloxy(lower)alkanoyl (e.g., phenoxyacetyl,    phenoxypropionyl and the like) and the like];-   heterocyclic acyl (e.g., heterocycliccarbonyl and the like);-   heterocyclicalkanoyl [e.g., heterocyclic(lower)alkanoyl (e.g.,    heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,    heterocyclicpentanoyl, heterocyclichexanoyl and the like) and the    like]; heterocyclicalkenoyl [e.g., heterocyclic(lower)alkenoyl    (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl,    heterocyclicpentenoyl, heterocyclichexenoyl and the like)];-   carbamoyl;-   alkylcarbamoyl [e.g., lower alkylcarbamoyl (e.g., methylcarbamoyl,    ethylcarbamoyl and the like)];-   alkoxycarbamoyl [e.g., lower alkoxycarbamoyl (e.g.,    methoxycarbamoyl, ethoxycarbamoyl and the like)] and the like;-   arylcarbamoyl [e.g., C₆₋₁₀ arylcarbamoyl (e.g., phenylcarbamoyl,    naphthylcarbamoyl and the like) and the like];-   arylthiocarbamoyl [e.g., C₆₋₁₀ arylthiocarbamoyl (e.g.,    phenylthiocarbamoyl, naphthylthiocarbamoyl and the like) and the    like];-   alkylsulfonyl [e.g., lower alkylsulfonyl (e.g., methylsulfonyl,    ethylsulfonyl and the like)];-   alkoxysulfonyl [e.g., lower alkoxysulfonyl (e.g., methoxysulfonyl,    ethoxysulfonyl and the like)] and the like;-   arylsulfonyl (e.g., phenylsulfonyl and the like);-   arylglyoxyloyl [e.g., C₆₋₁₀ arylglyoxyloyl (e.g., phenylglyoxyloyl,    naphthylglyoxyloyl and the like) and the like];-   heterocyclicglyoxyloyl; and the like. Each of these acyl is    optionally substituted by one or more suitable substituent(s).

Suitable “lower alkanoyl” may include formyl and alkanoyl in which thealkyl portion is straight or branched alkyl having 1 to 6 carbon atom(s)such as acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl,butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl,pentylcarbonyl, tert-pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl,isohexylcarbonyl, etc.

Suitable “cyclo(lower) alkylcarbonyl” may include cycloalkylcarbonyl, inwhich the cycloalkyl portion is cycloalkyl having 3 to 6 carbon atoms,such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, etc.

Suitable “lower alkoxycarbonyl” may include alkoxycarbonyl in which thealkyl portion is straight or branched alkyl having 1 to 6 carbon atom(s)such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,tert-pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl,isohexyloxycarbonyl, etc.

Suitable “arylcarbonyl” may include arylcarbonyl in which the arylportion is C₆-C₁₆ aryl such as phenylcarbonyl (benzoyl),naphthylcarbonyl, anthrylcarbonyl, pyrenylcarbonyl, phenanthrylcarbonyl,azulenylcarbonyl, etc.

Suitable “carbamoyl optionally mono- or di-substituted with loweralkyl(s)_(n) includes carbamoyl; N-(lower)alkylcarbamoyl in which thealkyl portion is alkyl having 1 to 6 carbon atom(s) such asN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert-butylcarbamoyl,N-pentylcarbamoyl, N-neopentylcarbamoyl, N-isopentylcarbamoyl,N-hexylcarbamoyl, etc.; N,N-di(lower)alkylcarbamoyl in which the alkylportions are each alkyl having 1 to 6 carbon atom(s) such asN,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-dibutylcarbamoyl, N,N-diisobutylcarbamoyl,N,N-di-tert-butylcarbamoyl, N,N-dipentylcarbamoyl,N,N-dineopentylcarbamoyl, N,N-diisopentylcarbamoyl,N,N-dihexylcarbamoyl, N-ethyl-N-methylcarbamoyl,N-methyl-N-propylcarbamoyl, N-butyl-N-methylcarbamoyl,N-methyl-N-isobutylcarbamoyl, etc. Each of these carbamoyl is optionallysubstituted by one or more suitable substituent(s).

Suitable “arylcarbamoyl” may include arylcarbamoyl in which the arylportion is C₆-C₁₆ aryl such as phenylcarbamoyl, naphthylcarbamoyl,anthrylcarbamoyl, pyrenylcarbamoyl, phenanthrylcarbamoyl,azulenylcarbamoyl, etc.

Suitable “aryl(lower)alkenyl” may include phenyl(C₂-C₆)alkenyl such asstyryl, phenylpropenyl, phenylbutenyl, phenylhexenyl, etc.,naphthyl(C₂-C₆)alkenyl such as naphthylvinyl, naphthylpropenyl,naphthylbutenyl, naphthylpentenyl, naphtylhexenyl, etc.

Suitable “amino” may include unsubstituted amino, and amino mono- ordi-substituted with substituent(s) selected from lower alkyl, loweralkanoyl, lower alkylsulfonyl and cycloalkyl such as N-(C₁-C₆alkyl)amino (e.g., N-methylamino, N-ethylamino, N-propylamino,N-(n-butyl)amino, N-isobutylamino, N-(t-butyl)amino, etc.), N-(C₁-C₆alkanoyl)amino (e.g., N-acetylamino, N-ethylcarbonylamino,N-propylcarbonylamino, N-(n-butylcarbonyl)amino,N-isobutylcarbonylamino, N-(t-butylcarbonyl)amino, etc.), N-(C₁-C₆)alkylsulfonylamino(e.g., N-methanesulfonylamino, N-ethanesulfonylamino,N-buthylsulfonylamino, etc.), N-(C₃-C₆ cycloalkyl)amino (e.g.,N-cyclopropylamino, N-cyclobutylamino, N-cyclopentylamino,N-cyclohexylamino, etc.), N,N-di(C₁-C₆ alkyl)amino (e.g.,N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, etc.), etc.

Suitable example of “heteroaryl” and “heteroar” moiety may include

-   -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 to 4 nitrogen atom(s), for        example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,        dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl        (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,        2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl,        2H-tetrazolyl, etc.), etc.;    -   unsaturated condensed heterocyclic group containing 1 to 4        nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,        indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,        benzotriazolyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to        3 nitrogen atom(s), for example, oxazolyl, isoxazolyl,        oxadiazolyl 20 (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,        1,2,5-oxadiazolyl, etc.), etc.;    -   unsaturated condensed heterocyclic group containing 1 or 2        oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,        benzoxazolyl, benzoxadiazolyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to        3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,        thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,        1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl,        etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 sulfur atom(s), for        example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,        benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing an oxygen atom, for example,        furyl etc.;    -   unsaturated condensed heterocyclic group containing an oxygen        atom, for example, benzofuranyl or benzotetrahydrofuranyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing an oxygen atom and 1 or 2        sulfur atom(s), for example, dihydrooxathiinyl, etc.;    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s), for example benzothienyl, benzodithiinyl, etc.;    -   unsaturated condensed heterocyclic group containing an oxygen        atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl,        etc.

Suitable example of “heterocyclyl” or “heterocyclyl” moiety may include

-   -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 to 4 nitrogen atom(s), for        example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,        azetidinyl, etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to        3 nitrogen atom(s), for example, morpholino, etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to        3 nitrogen atom(s), for example thiazolidinyl, thiomorpholinyl,        thiomorpholino, etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 oxygen atom(s), for        example, tetrahydrofuranyl, tetrahydropyranyl,        dioxacyclopentanyl, dioxacyclohexanyl, etc.;    -   saturated condensed heterocyclic group containing 1 to 3        nitrogen atom(s), for example, hexahydropyrrolopyrazinyl, etc.;        and the like, and this “heterocyclic group” may have one or more        suitable substituent(s) selected from the group consisting of        halogen, lower alkyl and aryl.

The term “arylene” refers to the diradical group derived from aryl(including substituted aryl) as defined above and is exemplified by1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and thelike.

The term “heteroarylene” refers to the diradical group derived fromheteroaryl (including substituted heteroaryl) as defined above and isexemplified by the groups 2,6-pyridylene, 3,6-pyridazinylene,2,5-pyrazinylene, 2,5-pyrimidinylene, 1,2-quinolinylene,1,8-quinolinylene, 1,4-benzofuranylene, 2,5-prudinylene, 2,5-indolenyl,and the like.

The term “cycloalkylene” refers to the diradical group derived fromcycloalkyl (including substituted cycloalkyl) as defined above and isexemplified by the groups 1,4-cyclohexylene, 1,3-cyclopentylene,1,3-cyclobutylene, and the like.

The term “heterocycloalkylene” refers to the diradical group derivedfrom heterocyclyl (including substituted heterocyclyl) as defined aboveand is exemplified by the groups piperidine, pyrrolidine, piperidone,pyrrolidone and the like.

The term “aryl-fused cycloalkylene” refers to the diradical groupderived from aryl-fused cyclo(lower)alkyl (including substitutedaryl-fused cyclo(lower)alkyl) as defined above and is exemplified by thegroups indanyl, tetrahydronaphthalene and the like.

Suitable “suitable substituent” may include lower alkyl, aryl,cyclo(lower)alkyl, cyclo(lower)alkenyl, heterocyclic group, and thelike.

Suitable “protected carboxy” or “protected carboxy” moiety in the“protected carboxy(lower)alkyl” may be a conventional protecting groupsuch as an esterified carboxy group, or the like, and concrete examplesof the ester moiety in said esterified carboxy group may be the onessuch as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester,isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentylester, hexyl ester, 1-cyclopropylethyl ester, etc.] which may havesuitable substituent(s), for example, lower alkanoyloxy(lower)alkylester [e.g. acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,1-acetoxyethyl ester,

-   1-propionyloxyethyl ester, pivaloyloxyethyl ester,    2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower    alkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.] or    mono(or di or tri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester,-   2,2,2-trichloroethyl ester, etc.]; higher alkyl ester [e.g. heptyl    ester, octyl ester,-   3,5-dimethyloctyl ester, 3,7-dimethyloctyl ester, nonyl ester, decyl    ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl    ester, pentadecyl ester, hexadecyl ester, heptadecyl ester,    octadecyl ester, nonadecyl ester, adamantyl ester, etc.];    -   lower alkenyl ester [e.g. (C₂-C₆)alkenyl ester (e.g. vinyl        ester, allyl ester, etc.)];    -   lower alkynyl ester [e.g. (C₂-C₆)alkynyl ester (e.g. ethynyl        ester, propynyl ester, etc.)];    -   ar(lower)alkyl ester which may have one or more suitable        substituent(s) [e.g. phenyl(lower)alkyl ester which may have 1        to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl,        or halo(lower)alkyl (e.g. benzyl ester,-   4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester,    phenethyl ester, trityl ester, benzhydryl ester,-   bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,-   4-hydroxy-3,5-di-tert-butylbenzyl ester,-   4-trifluoromethylbenzyl ester, etc.)];    -   aryl ester which may have one or more suitable substituent(s)        [e.g. phenyl ester which may have 1 to 4 lower alkyl, or halogen        (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester,        4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl        ester, etc.)];    -   cycloalkyloxycarbonyloxy(lower)/allyl ester which may have lower        alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester,-   cyclohexyloxycarbonyloxymethyl ester,-   cycloheptyloxycarbonyloxymethyl ester,-   1-methylcyclohexyloxycarbonyloxymethyl ester,-   1-(or 2-)[cyclopentyloxycarbonyloxy]ethyl ester,-   1-(or 2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or    2-)-[cycloheptyloxycarbonyloxy]ethyl ester, etc.), etc.];-   (5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,    (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,    (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,    (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or    2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or    2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or    2-)(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; and the like,    -   in which the preferred one may be lower alkyl ester, lower        alkanoyloxy(lower)alkyl ester, ar(lower)alkyl ester which may        have one or more suitable substituent(s),-   cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower    alkyl, higher alkyl ester, and    [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl ester;    -   and the more preferred one may be methyl ester, ethyl ester,        isobutyl ester, butyl ester, pentyl ester, hexyl ester, benzyl        ester; 4-trifluoromethylbenzyl ester, 4-chlorobenzyl ester,        adamantyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,        (1-cyclohexyloxycarbonyloxy)ethyl ester and pivaloyloxymethyl        ester, and the like, in which the preferred one may be        (C₁-C₄)alkyl ester, and the most preferred one may be ethyl        ester.

Suitable “amino protecting group” may include a conventional protectivegroup such as ar(lower)alkoxycarbonyl and lower alkoxycarbonyl, in whichthe preferred one may be phenyl(C₁-C₄)alkoxycarbonyl andfluorenyl(C₁-C₄)alkoxycarbonyl and (C₁-C₄)alkoxycarbonyl, and the mostpreferred one may be benzyloxycarbonyl, fluorenylmethoxycarbonyl andtert-butoxycarbonyl.

Suitable “hydroxy(lower)alkyl” may included hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxypentyl,hydroxyhexyl, and the like.

Suitable “formyl(lower)alkyl” may include formylmethyl, formylethyl,formylpropyl, formylisopropyl, formylbutyl, formylpentyl, formylhexyl,and the like.

Suitable “hydroxy protecting group” is as follows: lower alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc.), preferably methyl;

-   lower alkoxy(lower)alkyl (e.g. methoxymethyl, etc.);-   lower alkoxy(lower)alkoxy(lower)alkyl (e.g. 2-methoxyethoxymethyl,    etc.);-   ar(lower)alkyl in which the aryl portion is optionally substituted    with one or more suitable substituent(s) (e.g. benzyl (Bn),    p-methoxybenzyl, m,p-dimethoxybenzyl, etc.), preferably benzyl;-   ar(lower)alkoxy(lower)alkyl in which the aryl portion is optionally    substituted with one or more suitable substituent(s) (e.g.    benzyloxymethyl, p-methoxybenzyloxymethyl, etc.);-   (lower)alkylthio(lower)alkyl (e.g. methylthiomethyl,    ethylthiomethyl, propylthiomethyl, isopropylthiomethyl,    butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), etc.,    preferably methylthiomethyl;-   trisubstituted silyl such as tri(lower)alkylsilyl (e.g.    trimethylsilyl, triethylsilyl, tributylsilyl,    tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.), lower    alkyldiarylsilyl (e.g. methyldiphenylsilyl, ethyldiphenylsilyl,    propyldiphenylsilyl, tert-butyldiphenylsilyl (TBDPS), etc.), etc.,    preferably tert-butyldimethylsilyl (TBDMS) and    tert-butyldiphenylsilyl;-   heterocyclic group (e.g. tetrahydropyranyl, etc.);-   acyl as described below [e.g. aliphatic acyl such as lower alkanoyl    (e.g. acetyl, propanoyl, pivaloyl, etc.); aromatic acyl (e.g.    benzoyl (Bz), toluoyl, naphthoyl, fluorenylcarbonyl, etc.);-   lower alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,    propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,    isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,    hexyloxycarbonyl, etc.), etc.;-   ar(lower)alkoxycarbonyl in which the aryl portion is optionally    substituted with one or more suitable substituent(s) (e.g.    benzyloxycarbonyl, bromobenzyloxycarbonyl, etc.);-   lower alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.);-   lower alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl, etc.);-   ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropanoyl,    phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl,    naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl,    naphthylisobutanoyl, naphthylpentanoyl, naphthylhexanoyl, etc.);-   ar(lower)alkenoyl such as ar(C₃-C₆)alkenoyl (e.g. phenylpropenoyl,    phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl,    naphthylpropenoyl, naphthylbutenoyl, naphthylmethacryloyl,    naphthylpentenoyl, naphthylhexenoyl, etc.), etc.);-   lower alkenyl (e.g. vinyl, allyl, etc.); etc.

The preferable hydroxy protecting group for the present invention is,for example, tetrahydropyranyl, trimethylsilyl, t-butyldimethylsilyl,etc.

The following abbreviations are also used in the present specification:Boc (t-butyloxycarbonyl); HOBT or HOBt (1-hydroxybenzotriazole); WSCD(1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide); WSCD.HCl or EDCI(1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride); DMF(N,N-dimethylformamide); aq. (aqueous solution); Me (methyl); MeOH(methanol); MeCN (acetonitrile); Et (ethyl); Et₃N (triethylamine); EtOH(ethanol); IPE (diisopropyl ether); tBu (t-butyl); TsCl(p-toluenesulfonyl chloride); Ac (acetyl); AcOH (acetic acid); AcOEt(ethyl acetate); AcONH₄ (ammonium acetate); Ph (phenyl); DIEA(diisopropylethylamine); THP (tetrahydropyranyl); THF (tetrahydrofuran)and TFA or TFAOH (trifluoroacetic acid).

Test Method

In order to show the usefulness of the compound (I) of the invention,the pharmacological test result of the representative compound of thepresent invention is shown in the following.

Test 1: Determination of Histone Deacetylase Inhibitor Activity

The partial purification of human histone deacetylase, the preparationof [³H] acetyl histones, and the assay for histone deacetylase activitywere performed basically according to the method as proposed by Yoshidaet al. as follows.

Partial Purification of Human Histone Deacetylase

The human histone deacetylase was partially purified from human T cellleukemia Jurkat cells. Jurkat cells (5×10⁸ cells) were suspended in 40mL of the HDA buffer consisting of 15 mM potassium phosphate, pH 7.5, 5%glycerol and 0.2 mM EDTA. After homogenization, nuclei were collected bycentrifugation (35,000×g, 10 min) and homogenized in 20 mL of the samebuffer supplemented with 1 M (NH₄)₂SO₄. The viscous homogenate wassonicated and clarified by centrifugation (35,000×g, 10 min), and thedeacetylase was precipitated by raising the concentration of (NH₄)₂SO₄to 3.5 M. The precipitated protein was dissolved in 10 mL of the HDAbuffer and dialyzed against 4 liters of the same buffer. The dialyzatewas then loaded onto a DEAE-cellulose (Whatman DE52) column (25×85 mm)equilibrated with the same buffer and eluted with 300 mL of a lineargradient (0-0.6 M) of NaCl. A single peak of histone deacetylaseactivity appeared between 0.3 and 0.4 M NaCl.

Preparation of [³H] Acetyl Histone

To obtain [³H] acetyl-labeled histone as the substrate for the histonedeacetylase assay, 1×10⁸ cells of Jurkat in 20 mL of RPMI-1640 medium(supplemented with 10% FBS, penicillin (50 units/mL) and streptomycin(50 μg/mL)) were incubated with 300 MBq [³H] sodium acetate in thepresence of 5 mM sodium butyrate for 30 minutes in 5% CO₂-95% airatmosphere at 37° C. in a 75 cm² flask, harvested into a centrifuge tube(50 mL), collected by centrifugation at 1000 rpm for 10 minutes, andwashed once with phosphate-buffered saline. The washed cells weresuspended in 15 mL of ice-cold lysis buffer (10 mM Tris-HCl, 50 mMsodium bisulfite, 1% Triton X-100, 10 mM MgCl₂, 8.6% sucrose, pH 6.5).After Dounce homogenization (30 stroke), the nuclei were collected bycentrifugation at 1000 rpm for 10 minutes, washed 3 times with 15 mL ofthe lysis buffer, and once with 15 mL of ice-cooled washing buffer (10mM Tris-HCl, 13 mM EDTA, pH 7.4) successively. The pellet was suspendedin 6 mL of ice-cooled water using a mixer, and 68 μl of H₂SO₄ was addedto the suspension to give a concentration of 0.4 N. After incubation at4° C. for 1 hour, the suspension was centrifuged for 5 minutes at 15,000rpm, and the supernatant was taken and mixed with 60 mL of acetone.After overnight incubation at −20° C., the coagulated material wascollected by microcentrifugation, air-dried, and stored at −80° C.

Assay for Histone Deacetylase Activity

For the standard assay, 10 μl of [³H] acetyl-labeled histones were addedto 90 μl of the enzyme fraction, and the mixture was incubated at 25° C.for 30 minutes. The reaction was stopped by addition of 10 μl of HCl.The released [³H] acetic acid was extracted with 1 mL of ethyl acetate,and 0.9 mL of the solvent layer was taken into 10 mL of toluenescintillation solution for determination of radioactivity.

Test 2: Determination of T-Cell Growth Inhibitor Activity

The T lymphocyte blastogenesis test was performed in microtiter plateswith each well containing 1.5×10⁵ splenic cells of Lewis rats in 0.1 mLRPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 50 mM2-mercaptoethanol, penicilln (100 units/mL) and streptomycin (100μg/mL), to which Concanavalin A (1 μg/mL) was added. The cells wereincubated at 37° C. in a humidified atmosphere of 5% CO₂ for 72 hours.After the culture period, suppressive activities of the test compoundsin T lymphocyte blastogenesis were quantified by AlamarBlue (trademark)Assay. The test samples were dissolved in DMSO and further diluted withRPMI-1640 medium and added to the culture. The activities of the testcompounds were expressed as IC_(50.)

The results of those tests are shown in the Table 1. TABLE 1 HDACinhibitory activity and T-cell growth inhibitory activity of thecompound of the present invention Test 2: Test 1: T-cell HDAC growthinhibitory inhibitory activity activity Examples IC₅₀ (nM) IC₅₀ (nM)Example 3 <10 <25 Example 60 <10 <25 Example 74 <10 <25 Example 76 <10<25 Example 82 <10 <25 Example 116 <10 <25 Example 119 <10 <25 Example123 <10 <25 Example 174 <10 <25 Example 189 <10 <25

The pharmaceutical composition of the present invention comprisinghistone deacetylase inhibitor such as the compound (I) is useful as atherapeutic or prophylactic agent for diseases caused by abnormal geneexpression, such as inflammatory disorders, diabetes, diabeticcomplications, homozygous thalassemia, fibrosis, cirrhosis, acutepromyelocytic leukaemia (APL), protozoal infection, etc. Furthermore, itis useful as an antitumor agent or immunosuppressant, which prevents anorgan transplant rejection and autoimmune diseases as exemplified below:

-   rejection reactions by transplantation of organs or tissues such as    the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas,    small intestine, limb, muscle, nerve, intervertebral disc, trachea,    myoblast, cartilage, etc.;-   graft-versus-host reactions following bone marrow transplantation;    autoimmune diseases such as rheumatoid arthritis, systemic lupus    erythematosus, Hashimoto's thyroiditis, multiple sclerosis,    myasthenia gravis, type I diabetes, etc.; and-   infections caused by pathogenic microorganisms (e.g. Aspergillus    fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.).

Furthermore, pharmaceutical preparations of the histone deacetylaseinhibitor, such as the compound (I), are useful for the therapy orprophylaxis of the following diseases.

Inflammatory or hyperproliferative skin diseases or cutaneousmanifestations of immunologically-mediated diseases (e.g. psoriasis,atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheicdermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysisbullosa, urticaria, angioedema, vasculitides, erythema, dermaleosinophilia, lupus erythematosus, acne, alopecia areata, etc.);

-   autoimmune diseases of the eye (e.g. keratoconjunctivitis, vernal    conjunctivitis, uveitis associated with Behcet's disease, keratitis,    herpetic keratitis, conical keratitis, corneal epithelial dystrophy,    keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's    ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis    sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine    ophthalmopathy, etc.);-   reversible obstructive airways diseases [asthma (e.g. bronchial    asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust    asthma, etc.), particularly chronic or inveterate asthma (e.g. late    asthma, airway hyper-responsiveness, etc.), bronchitis, etc.];-   mucosal or vascular inflammations (e.g. gastric ulcer, ischemic or    thrombotic vascular injury, ischemic bowel diseases, enteritis,    necrotizing enterocolitis, intestinal damages associated with    thermal burns, leukotriene B4-mediated diseases, etc.);-   intestinal inflammations/allergies (e.g. coeliac diseases,    proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's    disease, ulcerative colitis, etc.);-   food-related allergic diseases with symptomatic manifestation remote    from the gastrointestinal tract (e.g. migrain, rhinitis, eczema,    etc.);-   renal diseases (e.g. intestitial nephritis, Goodpasture's syndrome,    hemolytic uremic syndrome, diabetic nephropathy, etc.);-   nervous diseases (e.g. multiple myositis, Guillain-Barre syndrome,    Meniere's disease, multiple neuritis, solitary neuritis, cerebral    infarction, Alzheimer's disease, Parkinson's disease, amyotrophic    lateral sclerosis (ALS), radiculopathy, etc.);-   cerebral ischemic diseases (e.g., head injury, hemorrhage in brain    (e.g., subarachnoid hemorrhage, intracerebral hemorrhage, etc.),    cerebral thrombosis, cerebral embolism, cardiac arrest, stroke,    transient ischemic attack (TIA), hypertensive encephalopathy, etc.);-   endocrine diseases (e.g. hyperthyroidism, Basedow's disease, etc.);-   hematic diseases (e.g. pure red cell aplasia, aplastic anemia,    hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune    hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic    anemia, anerythroplasia, etc.);-   bone diseases (e.g. osteoporosis, etc.);-   respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis,    idiopathic interstitial pneumonia, etc.);-   skin diseases (e.g. dermatomyositis, leukoderma vulgaris, ichthyosis    vulgaris, photosensitivity, cutaneous T-cell lymphoma, etc.);-   circulatory diseases (e.g. arteriosclerosis, atherosclerosis,    aortitis syndrome, polyarteritis nodosa, myocardosis, etc.);-   collagen diseases (e.g. scleroderma, Wegener's granuloma, Sjögren's    syndrome, etc.);-   adiposis;-   eosinophilic fasciitis;-   periodontal diseases (e.g. damage to gingiva, periodontium, alveolar    bone or substantia ossea dentis, etc.);-   nephrotic syndrome (e.g. glomerulonephritis, etc.);-   male pattern alopecia, alopecia senile;-   muscular dystrophy;-   pyoderma and Sezary syndrome;-   chromosome abnormality-associated diseases (e.g. Down's syndrome,    etc.);-   Addison's disease;-   active oxygen-mediated diseases {e.g. organ injury [e.g. ischemic    circulation disorders of organs (e.g. heart, liver, kidney,    digestive tract, etc.) associated with preservation,    transplantation, ischemic diseases (e.g. thrombosis, cardial    infarction, etc.), etc.];-   intestinal diseases (e.g. endotoxin shock, pseudomembranous colitis,    drug- or radiation-induced colitis, etc.);-   renal diseases (e.g. ischemic acute renal insufficiency, chronic    renal failure, etc.);-   pulmonary diseases (e.g. toxicosis caused by pulmonary oxygen or    drugs (e.g. paracort, bleomycin, etc.), lung cancer, pulmonary    emphysema, etc.);-   ocular diseases (e.g. cataracta, iron-storage disease (siderosis    bulbi), retinitis, pigmentosa, senile plaques, vitreous scarring,    corneal alkali burn, etc.);-   dermatitis (e.g. erythema multiforme, linear immunoglobulin A    bullous dermatitis, cement dermatitis, etc.); and-   other diseases (e.g. gingivitis, periodontitis, sepsis,    pancreatitis, diseases caused by environmental pollution (e.g. air    pollution, etc.), aging, carcinogen, metastasis of carcinoma,    hypobaropathy, etc.));-   diseases caused by histamine release or leukotriene C4 release;    restenosis of coronary artery following angioplasty and prevention    of postsurgical adhesions;-   autoimmune diseases and inflammatory conditions (e.g., primary    mucosal edema, autoimmune atrophic gastritis, premature menopause,    male sterility, juvenile diabetes mellitus, pemphigus vulgaris,    pemphigoid, sympathetic ophthalmitis, lens-induced uveitis,    idiopathic leukopenia, active chronic hepatitis, idiopathic    cirrhosis, discoid lupus erythematosus, autoimmune orchitis,    arthritis (e.g. arthritis deformans, etc.), polychondritis, etc.);    Human Immunodeficiency Virus (HIV) infection, AIDS;-   allergic conjunctivitis;-   hypertrophic cicatrix, keloid due to trauma, burn or surgery, etc.

Therefore, the pharmaceutical composition of the present invention isuseful for the therapy and prophylaxis of liver diseases [e.g.immunogenic diseases (e.g. chronic autoimmune liver diseases such asautoimmune hepatic diseases, primary biliary cirrhosis, sclerosingcholangitis, etc.), partial liver resection, acute liver necrosis (e.g.necrosis caused by toxins, viral hepatitis, shock, anoxia, etc.),hepatitis B, non-A non-B hepatitis, hepatocirrhosis, hepatic failure(e.g. fulminant hepatitis, late-onset hepatitis, “acute-on-chronic”liver failure (acute liver failure on chronic liver diseases, etc.),etc.), etc.].

The pharmaceutical composition of the present invention can be used inthe form of pharmaceutical preparation, for example, in a solid,semisolid or liquid form, which contains the histone deacetylaseinhibitor, such as the compound (I), as an active ingredient inadmixture with an organic or inorganic carrier or excipient suitable forexternal, enteral or parenteral administrations. The active ingredientmay be compounded, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, injections, ointments,liniments, eye drops, lotion, gel, cream, and any other form suitablefor use.

The carriers those can be used for the present invention include water,glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea and other carriers suitable for use in manufacturingpreparations in a solid, semisolid, or liquid form. Furthermore,auxiliary, stabilizing, thickening, solubilizing and coloring agents andperfumes may be used.

For applying the composition to human, it is preferable to apply it byintravenous, intramuscular, topical or oral administration, or by avascular stent impregnated with the compound (I). While the dosage oftherapeutically effective amount of the histone deacetylase inhibitor,such as the compound (I), varies from and also depends upon the age andcondition of each individual patient to be treated, when an individualpatient is to be treated, in the case of intravenous administration, adaily dose of 0.01-10 mg of the histone deacetylase inhibitor, such asthe compound (I), per kg weight of human being, in the case ofintramuscular administration, a daily dose of 0.1-10 mg of the histonedeacetylase inhibitor, such as the compound of the formula (I), per kgweight of human being, and in the case of oral administration, a dailydose of 0.5-50 mg of the histone deacetylase inhibitor, such as thecompound (I), per kg weight of human being, is generally given fortreatment.

During the preparation of the above-mentioned pharmaceuticaladministration forms, the compound (I) or a salt thereof can also becombined together with other immunosuppressive substances, for examplerapamycin, mycophenolic acid, cyclosporin A, tacrolimus or brequinarsodium.

Hereinafter the reactions in each Preparations and Examples forpreparing the compound (I) of the present invention are explained inmore detail. The invention should not be restricted by the followingPreparations and Examples in any way.

Preparation 1

A mixture of methyl 6-chloronicotinate (5.0 g),1-benzyl-3-aminopyrrolidine (6.16 g) and K₂CO₃ (4.83 g) in DMF (20 ml)was stirred at 100% for 10 hours under atmospheric pressure of nitrogen.The reaction mixture was poured into a mixture of AcOEt and water andthe organic layer was washed with brine and dried over MgSO₄. Thesolvent was evaporated in vacuo and the residue was chromatographed onsilicagel eluting with AcOEt-MeOH (97:3). The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive methyl 6-[(1-benzylpyrrolidin-3-yl)amino]nicotinate (4.17 g)

NMR (DMSO-d₆, δ): 1.58-1.71 (1H, m), 2.17-2.34 (1H, m), 2.37-2.89 (4H,m), 3.51 (2H, s), 3.65 (2H, s), 4.39 (1H, m), 6.42 (1H, d, J=8.80 Hz),7.19-7.33 (5H, m), 7.59 (1H, d, J=6.78 Hz), 7.80 (1H, dd, J=2.20 Hz and8.80 Hz), 8.56 (1H, d, J=2.20 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 1.

Preparation 2

Methyl 6-[N-(1-benzylpyrrolidin-3-yl)-N-methylamino]nicotinate

NMR (DMSO-d₆, δ): 173-1.76 ((1H, m), 2.23-2.44 (2H, m), 2.48-2.67 (2H,m), 2.81-2.85 (11H, m), 2.85 (3H, s), 3.53, 3.63 (2H, ABq, J=13.02 Hz),3.66 (3H, s), 5.34-5.39 (1H, m), 6.66 (1H, d, J=90.6 Hz), 7.20-7.34 (5H,m), 7.92 (1H, dd, J=2.06 Hz, 9.06 Hz), 8.63 (1H, d, J=2.06 Hz)

Preparation 3

Methyl 6-[[1-(tert-butoxycarbonyl)piperidin-4-yl]-amino]nicotinate

NMR (CDCl₃, δ): 1.47(9H, s), 1.15-2.08(4H, m), 2.79-3.02(2H, m),3.90(3H, s), 3.96-4.10(2H, m), 4.95(1H, d, J=7.7 Hz), 6.35(1H, d, J=8.8Hz), 7.98(1H, dd, J=2.0, 8.8 Hz), 8.73(1H, d, J=2.0 Hz)

Mass (APCI): 358 (M+H)+

Preparation 4

Benzyl 6-[1-(tert-butoxycarbonyl)-4-piperidylamino]-5-chloronicotinate

NMR (DMSO-d₆, δ): 1.40(9H, s), 1.48-1.60(2H, m), 1.70-1.90(2H, m),2.60-2.90(2H, m), 3.85-4.01(2H, m), 4.10-4.40(1H, m), 5.30(2H, s),7.05(1H, d, J=8.2 Hz), 7.30-7.47(5H, m), 7.97(1H, d, J=2.0 Hz), 8.60(1H,d, J=2.0 Hz)

Mass (APCI): 445(M+Na)+

Preparation 5

Methyl 6-[[1-(tert-butoxycarbonyl)-4-piperidyl](methyl)amino]-nicotinate

NMR (DMSO-d₆, δ): 1.41(9H, s), 1.50-1.80(4H, m), 2.65-2.85(2H, m),2.89(3H, s), 3.78(3H, s), 4.05-4.20(2H, m), 4.60-4.80(1H, m), 6.72(1H,d, J=8.8 Hz), 7.94(1H, dd, J=2.0, 8.8 Hz), 8.64(1H, d, J=2.0 Hz)

Mass (APCI): 372(M+Na)+

Preparation 6

Lithium aluminium hydride (256 mg) was added to absolution of methyl6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinate (1.4 g) in THF (50 ml) withstirring at 5-10′ under atmospheric pressure of nitrogen, and thereaction mixture was stirred at 5-20° C. for 4 hours. The reactionmixture was cooled at 5° C. and water (0.26 ml), 15% NaOH solution (0.26ml) and water (0.72 ml) was added, the resultant mixture was stirred atambient temperature for 20 minutes. The reaction mixture was filtratedand the filtrate was dried over MgSO₄. The solvent was evaporated invacuo and the residue was chromatographed on silicagel eluting withAcOEt-MeOH (85:15). The eluted fractions containing the desired productwere collected and evaporated in vacuo to give{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}methanol (0.96 g)

NMR (DMSO-d₆, δ): 1.58-1.65 (1H, m), 2.06-2.52 (3H, m), 2.59-2.81 (2H,m), 3.42 (2H, s), 4.18-4.37 (1H, m), 4.26 (2H, d, J=5.28 Hz), 4.87 (1H,t, J=5.28 Hz), 6.43 (1H, d, J=8.54 Hz), 6.53 (1H, d, J=6.80 Hz),7.18-7.36 (6H, m), 7.85 (1H, d, J=2.10 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 6.

Preparation 7

(6-[(1-Benzyl-3-pyrrolidinyl)(methyl)amino]-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.67-1.73 (1H, m), 2.07-2.11 (1H, m), 2.24-2.33 (1H,m), 2.43-2.58 (2H, m), 2.76-2.83 (1H, m), 2.90 (3H, s), 3.52, 3.63 (2H,ABq, J=13.08 Hz), 4.32 (2H, d, J=4.78 Hz), 4.94 (1H, J=4.78 Hz),5.18-5.29 (1H, m), 6.58 (1H, d, J=8.74 Hz), 7.21-7.47 (5H, m), 7.44 (1H,dd, J=2.22 Hz, 8.74 Hz), 7.98 (1H, d, J=2.22 Hz)

Preparation 8

(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.59-1.65 (1H, m), 2.09-2.51 (3H, m), 2.59-2.63 (1H,m), 2.73-2.81 (1H, m), 3.53, 3.59 (2H, ABq, J=12.98 Hz), 4.23 (2H, d,J=5.34 Hz), 4.18-4.28 (1H, m), 4.88 (1H, t, J=5.34 Hz), 6.44 (1H, d,J=8.52 Hz), 6.53 (1H, d, J=6.84 Hz), 7.16-7.36 (6H, m), 7.85 (1H, d,J=2.10 Hz)

Preparation 9

(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.59-1.66 (1H, m), 2.16-2.55 (3H, m), 2.56-2.60 (1H,m), 2.63-2.81 (1H, m), 3.44-3.63 (2H, m), 4.19-4.35 (3H, m), 4.89 (1H,brs), 6.44 (1H, d, J=8.50 Hz), 6.54 (1H, d, J=6.82 Hz), 7.18-7.34 (6H,m), 7.87 (1H, d, J=2.04 Hz)

Preparation 10

tert-Butyl4-{[5-(hydroxymethyl)-2-pyridyl]amino}-1-piperidinecarboxylate

NMR (CDCl₃, δ): 1.20-1.40(2H, m), 1.47(9H, s), 1.98-2.06(2H, m),2.84-3.01(2H, m), 3.76-4.00(1H, m), 4.00-4.39(2H, m), 4.40(1H, d, J=15.8Hz), 4.52(2H, s), 6.38(1H, d, J=8.8 Hz), 7.46(1H, dd, J=2.0, 8.8 Hz),8.01(1H, d, J=2.0 Hz)

Mass (APCI): 308(M+H)+

Preparation 11

tert-Butyl4-{[3-chloro-5-(hydroxymethyl)-2-pyridyl]amino}-1-piperidinecarboxylate

Mass (APCI): 343(M+H)+

Preparation 12

tert-Butyl4-[[5-(hydroxymethyl)-2-pyridyl](methyl)amino]-1-piperidinecarboxylate

NMR (DMSO-d₆, δ): 1.41(9H, s), 1.54-1.63(4H, m), 2.78(3H, s),2.75-2.99(2H, m), 4.01-4.20(2H, m), 4.32(2H, d, J=5.3 Hz), 4.50-4.80(1H,m), 4.90-4.96(1H, m), 6.61(1H, d, J=8.8 Hz), 7.46(1H, dd, J=2.0, 8.8Hz), 8.00(1H, d, J=2.0 Hz)

Mass (APCI): 344(M+Na)+

Preparation 13

A mixture of (6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl)methanol(0.96 g) and MnO₂ (2.951 g) in AcOEt (50 ml) was refluxed under stirringfor 1.5 hour. After removal of the insoluble material, and the solventwas evaporated in vacuo to give6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g)

NMR (DMSO-d₆, δ): 1.66-1.72 (1H, m), 2.06-2.52 (3H, m), 2.62-2.82 (2H,m), 3.60 (2H, s), 4.39-4.45 (1H, m), 6.58 (1H, d, J=8.80 Hz), 7.16-7.32(5H, m), 7.73 (1H, dd, J=2.18 Hz, 8.80 Hz), 7.93 (1H, d, J=5.52 Hz),8.47 (1H, d, J=2.18 Hz), 9.66 (1H, s)

The following compounds were obtained according to a similar manner tothat of Preparation 13.

Preparation 14

6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}nicotinaldehyde

NMR (DMSO-d₆, δ): 1.66-1.99 (1H, m), 2.23-2.38 (1H, m), 2.41-2.52 (2H,m), 2.61-2.82 (2H, m), 3.52 (2H, s), 4.39-4.45 (1H, m), 6.58 (1H, d,J=8.84 Hz), 7.16-7.33 (5H, m), 7.73 (1H, dd, J=2.20 Hz, 8.84 Hz), 7.90(1H, d, J=6.64 Hz), 8.47 (1H, d, J=2.20 Hz), 9.66 (1H, s)

Preparation 15

6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}nicotinaldehyde

NMR (DMSO-d₆, δ): 1.66-2.00 (1H, m), 2.21-2.26 (1H, m), 2.38-2.52 (2H,m), 2.61-2.82 (2H, m), 3.52 (2H, s), 4.45 (1H, m), 6.58 (1H, d, J=8.88Hz), 7.16-7.33 (5H, m), 7.73 (1H, dd, J=2.18 Hz, 8.88 Hz), 7.90 (1H, d,J=6.72 Hz), 8.47 (1H, d, J=2.18 Hz), 9.66 (1H, s)

Preparation 16

6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde

NMR (DMSO-d₆, δ): 1.86-1.96 (1H, m), 2.00-2.26 (1H, m), 2.43-2.61 (3H,m), 2.61-2.68 (1H, m), 3.60 (2H, s), 4.60-4.67 (1H, m), 7.19-7.37 (5H,m), 7.91 (1H, d, J=1.88 Hz), 8.52 (1H, d, J=1.88 Hz), 9.72 (1H, s)

Preparation 17

6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde

NMR (DMSO-d₆, δ): 1.78-1.99 (1H, m), 2.18-2.30 (1H, m), 2.42-2.68 (3H,m), 2.82-2.90 (1H, m), 3.60 (2H, s), 4.59-4.64 (1H, m), 7.19-7.37 (6H,m), 7.91 (1H, d, J=1.96 Hz), 8.52 (1H, d, J=1.96 HZ), 9.72 (1H, s)

Preparation 18

6-[(1-Benzyl-3-pyrrolidinyl)(methyl)amino]-nicotinaldehyde

NMR (DMSO-d₆, δ): 1.65-1.78 (1H, m), 2.20-2.31 (2H, m), 2.45-2.54 (2H,m), 2.63-2.70 (1H, m), 2.82-2.89 (1H, m), 3.07 (3H, s), 3.55, 3.64 (2H,ABq, J=13.04 Hz), 5.40-5.42 (1H, m), 6.76 (1H, d, J=9.10 Hz),7.23-7.35)₅H, m), 7.76 (1H, dd, J=2.24 Hz, 9.10 Hz), 8.56 (1H, d, J=2.24Hz), 9.74 (1H, s)

Preparation 19

tert-Butyl 4-[(5-formyl-2-pyridyl)amino]-1-piperidinecarboxylate

NMR (CDCl₃, δ): 1.2-1.47(11H, m), 2.0-2.10(2H, m), 2.88-3.21(2H, m),3.92-4.23(3H, m), 5.04(1H, d, J=15.8 Hz), 6.42(1H, d, J=8.8 Hz),7.88(1H, dd, J=2.0, 8.8 Hz), 8.51(1H, d, J=2.0 Hz), 9.77(1H, s)

Mass (APCI): 328(M+Na)+

Preparation 20

tert-Butyl4-[(3-chloro-5-formyl-2-pyridyl)amino]-1-piperidinecarboxylate

NMR (DMSO-d₆, δ): 1.40(9H, s), 1.48-1.60(2H, m), 1.70-1.90(2H, m),2.60-2.90(2H, m), 3.85-4.01(2H, m), 4.10-4.40(1H, m), 7.26(1H, d, J=8.2Hz), 7.93(1H, d, J=2.0 Hz), 8.54(1H, d, J=2.0 Hz), 9.72(1H, s)

Mass (APCI): 362(M+Na)+

Preparation 21

tert-Butyl 4-[(5-formyl-2-pyridyl)(methyl)amino]-1-piperidinecarboxylate

NMR (DMSO-d₆, δ): 1.42(9H, s), 1.56-1.75(4H, m), 2.70-2.80(2H, m),2.94(3H, s), 4.03-4.20(2H, m), 4.70-4.90(1H, m), 6.82(1H, d, J=8.8 Hz),7.88(1H, dd, J=2.0, 8.8 Hz), 8.59(1H, d, J=2.0 Hz), 9.72(1H, s)

Mass (APCI): 342(M+Na)+

Preparation 22

5-Chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-nicotinaldehyde

Mass (ESI): 334(M+H)+

Preparation 23

5-Chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-nicotinaldehyde

NMR (DMSO-d₆, δ): 1.72-1.85(1H, m), 2.08-2.85(5H, m), 2.27(3H, s),3.52(2H, s), 4.51-4.64(1H, m), 7.10(2H, d, J=8.8 Hz), 7.19(2H, d, J=8.8Hz), 7.28(1H, d, J=7.0 Hz), 7.91(1H, d, J=2.0 Hz), 8.52(1H, d, J=2.0Hz), 9.72(1H, s)

Mass (APCI): 330(M+H)+

Preparation 24

5-Chloro-6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}nicotinaldehyde

Mass (ESI): 346(M+H)+

Preparation 25

A solution of diethylphosphonoacetic acid ethyl ester (896 mg) in THF(10 ml) was added dropwise to a mixture of 60% sodium hydride in oil(170 mg) in THF (20 mL) with stirring at 10-20° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at ambienttemperature for 30 minutes. A solution of6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g) in THF (10ml) solution was added the above mixture, and resultant mixture wasstirred at ambient temperature for 1.5 hour. The reaction mixture waspoured into a mixture of AcOEt-H₂O and the organic layer was washed withbrine and dried over MgSO₄. The solvent was evaporated in vacuo and theresidue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5).The eluted fractions containing the desired product were collected andevaporated in vacuo to give ethyl(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylate (0.83 g).

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.06 Hz), 1.50-1.73 (1H, m), 2.36-2.52(3H, m), 2.73-2.77 (2H, m), 3.57 (2H, s), 4.14 (2H, q, J=7.06 Hz), 4.30(1H, m), 6.31 (1H, d, J=15.80 Hz), 6.52 (1H, d, J=8.86 Hz), 7.18-7.36(5H, m), 7.49 (1H, d, J=15.80 Hz), 7.77 (1H, dd, J=2.10 Hz, 8.86 Hz),8.20 (1H, d, J=2.10 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 25.

Preparation 26

Ethyl(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)(methyl)amino]-3-pyridyl}acrylate

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.06 Hz), 1.56-1.82 (1H, m), 2.27-2.61(4H, m), 2.83-2.84 (1H, m), 3.00 (3H, s), 3.58 and 3.63 (2H, ABq,J=13.02 Hz), 5.25-5.39 (1H, m), 6.38 (1H, d, J=15.94 Hz), 6.67 (1H, d,J=9.06 Hz), 7.19-7.34 (5H, m), 7.53 (1H, d, J=15.94 Hz), 7.90 (1H, dd,J=2.26 Hz, 9.06 Hz), 8.30 (1H, d, J=2.26 Hz)

Preparation 27

Ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 125 (3H, t, J=7.06 Hz), 1.56-1.78 (1H, m), 2.10-2.20(1H, m), 2.34-2.52 (2H, m), 2.52-2.78 (2H, m), 3.57 (2H, s), 4.15 (2H,q, J=7.06 Hz), 4.36 (1H, m), 6.41 (1H, d, J=15.92 Hz), 6.52 (1H, d,J=8.82 Hz), 7.18-7.37 (6H, m), 7.50 (1H, d, J=15.92 Hz), 7.78 (1H, dd,J=2.10 Hz, 8.82 Hz), 8.20 (1H, d, J=2.10 Hz)

Preparation 28

Ethyl (2E)-3-(6-{[(3S)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.06 Hz), 1.56-1.73 (1H, m), 2.21-2.37(1H, m), 2.39-2.52 (2H, m), 2.73-2.78 (2H, m), 3.57 (2H, s), 4.15 (2H,q, J=7.06 Hz), 4.36 (1H, m), 6.31 (1H, d, J=15.90 Hz), 6.52 (1H, d,J=8.86 Hz), 7.18-7.36 (5H, m), 7.50 (1H, d, J=15.90 Hz), 7.77 (1H, dd,J=2.14 Hz, 8.86 Hz), 8.20 (1H, d, J=2.14 Hz)

Preparation 29

Ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.06 Hz), 1.84-1.97 (1H, m), 2.00-2.30(1H, m), 2.39-2.53 (2H, m), 2.62-2.78 (1H, m), 2.79-2.87 (1H, m), 3.59(2H, s), 4.16 (2H, q, J=7.06 Hz), 4.49-4.56 (1H, m), 6.49 (1H, d,J=15.96 Hz), 6.73 (1H, d, J=6.90 Hz), 7.19-7.32 (5H, m), 7.51 (1H, d,J=15.96 Hz), 8.10 (1H, d, J=1.88 Hz), 8.26 (1H, d, J=1.88 Hz)

Preparation 30

Ethyl(2E)-3-(6-{[(3S)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.06 Hz), 1.84-1.99 (1H, m), 2.16-2.30(1H, m), 2.39-2.46 (2H, m), 2.62-2.66 (1H, m), 2.79-2.88 (1H, m), 3.58(2H, s), 4.16 (2H, q, J=7.06 Hz), 4.49-4.56 (1H, m), 6.49 (1H, D,J=15.98 Hz), 6.72 (1H, d, J=6.92 Hz), 7.18-7.36 (5H, m), 7.51 (1H, d,J=15.98 Hz), 8.10 (1H, d, J=1.96 Hz), 8.26 (1H, d, J=1.96 Hz)

Preparation 31

tert-Butyl4-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxylate

NMR (DMSO-d₆, δ): 1.33(3H, t, J=7.1 Hz), 1.36-1.42(2H, m), 1.47(9H, s),2.00-2.08(2H, m), 2.88-3.02(2H, m), 3.80-4.00(1H, m), 4.03-4.20(2H, m),4.24(2H, q), 4.6(1H, m), 6.22(1H, d, J=16.0 Hz), 6.38(1H, d, J=8.7 Hz),7.57(1H, d, J=16.0 Hz), 7.61(1H, dd, J=2.4, 8.7 Hz), 8.19(1H, d, J=2.4Hz)

Mass (APCI): 398(M+H)+

Preparation 32

tert-Butyl4-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxylate

Mass (ESI): 410(M+H)+

Preparation 33

tert-Butyl4-[{5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}-(methyl)amino]-1-piperidinecarboxylate

Mass (ESI): 390(M+H)+

Preparation 34

Ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

Mass (ESI): 404(M+H)+

Preparation 35

Ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.70-1.95(1H, m), 2.10-2.29(1H,m), 2.27(3H, s), 2.35-2.84(4H, m), 3.53(2H, s), 4.15(2H, q, J=7.4 Hz),4.44-4.54(1H, m), 6.48(1H, d, J=16.0 Hz), 6.72(1H, d, J=7.0 Hz),7.10(2H, d, J=8.8 Hz), 7.18(2H, d, J=8.8 Hz), 7.50(1H, d, J=16.0 Hz),8.10(1H, d, J=2.0 Hz), 8.26(1H, d, J=2.0 Hz)

Mass (APCI): 400(M+H)+

Preparation 36

Ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.45-1.85(9H, m), 1.90-2.10(2H, m), 2.70-2.85(2H, m),3.44(2H, s), 3.45-3.58(1H, m), 3.85-4.15(2H, m), 4.90(1H, s), 6.32(1H,d, J=16.0 Hz), 6.51(1H, d, J=7.0 Hz), 7.10-7.478(5H, m), 7.84(1H, s),8.21(1H, s), 11.09(1H, brs)

Preparation 37

A mixture of ethyl(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-acrylate (830 mg)and 1N NaOH solution (4.7 ml) in MeOH (20 ml) was stirred at 70-75° C.for 2 hours. The reaction mixture was evaporated in vacuo, and theresidue was dissolved with saturated NaCl solution (20 ml). The solutionwas adjusted to pH6.0 with aq. HCl, and the precipitate was collected byfiltration to give(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-acrylic acid (700mg)

NMR (DMSO-d₆, δ): 1.92-2.01 (1H, m), 2.30-2.43 (1H, m), 2.94-3.52 (4H,m), 4.29 (2H, s), 4.53-4.56 (1H, m), 6.28 (1H, d, J=15.82 Hz), 6.62 (1H,d, J=8.78 Hz), 7.39-7.64 (6H, m), 7.75-7.83 (2H, m), 8.20 (1H, d, J=2.00Hz), 11.92 (1H, m)

The following compounds were obtained according to a similar manner tothat of Preparation 37.

Preparation 38

(2E)-3-{6-[(1-Benzyl-3-pyrrolidinyl)(methyl)amino]-3-pyridyl}acrylicacid

NMR (DMSO-d₆, δ): 2.08-2.16 (1H, m), 2.80-3.60 (5H, m), 4.23 (2H, brs),5.54-5.61 (1H, m), 6.35 (1H, d, J=15.92 Hz), 6.72 (1H, d, J=9.02 Hz),7.39-7.62 (6H, m), 7.92 (1H, dd, J=2.04 Hz, 9.06 Hz), 8.32 (1H, d,J=2.04 Hz)

Preparation 39

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid

NMR (DMSO-d₆, δ): 1.87-1.93 (1H, m), 2.28-2.38 (1H, m), 2.83-3.37 (4H,m), 4.15 (2H, s), 6.29 (1H, d, J=15.92 Hz), 6.62 (1H, d, J=8.88 Hz),7.32-7.43 (3H, m), 7.51-7.58 (2H, m), 7.77-7.81 (2H, m), 8.20 (1H, d,J=1.94 Hz)

Preparation 40

(2E)-3-(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid

NMR (DMSO-d₆, δ): 1.98-2.04 (1H, m), 2.31-2.38 (1H, m), 2.95-3.56 (4H,m), 4.35 (2H, s), 4.55-4.58 (1H, m), 6.29 (1H, d, J=15.86 Hz), 6.63 (1H,d, J=8.82 Hz), 7.40-7.67 (6H, m), 8.10 (1H, dd, J=2.08 Hz, 8.82 Hz),7.92 (1H, brs), 8.20 (1H, d, J=2.08 Hz)

Preparation 41

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.76-1.99 (1H, m), 2.19-2.24 (1H, m), 2.48-2.77 (3H,m), 2.91-2.96 (1H, m), 3.60 (2H, s), 4.49-4.56 (1H, m), 6.39 (1H, d,J=15.88 Hz), 6.74 (1H, d, J=6.88 Hz), 7.21-7.35 (5H, m), 7.45 (1H, d,J=15.88 Hz), 8.07 (1H, d, J=1.82 Hz), 8.24 (1H, d, J=1.82 Hz)

Preparation 42

(2E)-3-(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.89-1.99 (1H, m), 2.19-2.27 (1H, m), 2.58-3.07 (4H,m), 3.74 (2H, s), 4.44-4.59 (1H, m), 6.40 (1H, d, J=15.96 Hz), 6.82 (1H,d, J=6.88 Hz), 7.25-7.40 (5H, m), 7.46 (1H, d, J=15.96 Hz), 8.08 (1H, d,J=1.82 Hz), 8.24 (1H, d, J=1.82 Hz)

Preparation 43

(2E)-3-(6-{[(3R)-1-(4-Methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.60-1.95 (1H, m), 2.10-2.40 (1H, m), 2.50-4.00 (6H,m), 3.74 (3H, s), 4.30-4.60 (1H, m), 6.24 (1H, d, J=6 Hz), 6.54 (1H, d,J=8.8 Hz), 6.92 (2H, d, J=8.5 Hz), 7.30-7.60 (4H, m), 7.78 (1H, dd,J=2.1 Hz, J=8.8 Hz), 8.18 (1H, d, J=2.1 Hz), 11.80 (1H, br)

MASS(API-ES); 354 (M+H)+

Preparation 44

(2E)-3-(6-{[(3R)-1-(4-Fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.50-1.80 (1H, m), 2.05-2.90 (5H, m), 3.50-3.70 (2H,m), 4.20-4.50 (1H, m), 6.22 (1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz),7.05-7.18 (2H, m), 7.30-7.40 (3H, m), 7.43 (1H, d, J=6 Hz), 7.74 (1H,dd, J=2.1 and 8.8 Hz), 8.15 (1H, d, J=2.1 Hz)

MASS(API-ES, Nega); 340 (M−H)+

Preparation 45

(2E)-3-(6-{[(3R)-1-(4-Chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.60-1.85 (1H, m), 2.10-3.00 (5H, m), 3.10-3.90 (2H,m), 4.25-4.50 (1H, m), 6.23 (1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz),7.30-7.55 (6H, m), 7.75 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.17 (1H, d, J=2.1Hz)

MASS(API-ES); 358 (M+H)+360

Preparation 46

(2E)-3-(6-{[(3R)-1-(4-Methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.60-1.90 (1H, m), 2.10-3.15 (5H, m), 2.28 (3H, s),3.50-3.95 (2H, m), 4.25-4.50 (1H, m), 6.24 (1H, d, J=16 Hz), 6.54 (1H,d, J=8.8 Hz), 7.15 (2H, d, J=7.8 Hz), 7.29 (2H, d, J=7.8 Hz), 7.44 (1H,d, J=16 Hz), 7.48(1H, m), 7.76 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.17 (1H,d, J=2.1 Hz)

MASS(API-ES); 338 (M+H)+

Preparation 47

(2E)-3-(6-{[(3R)-1-(Cyclopropylmethyl)-3-pyrrolidinyl]-amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 0.05-0.25 (2H, m), 0.40-0.60 (2H, m), 0.80-1.05 (1H,m), 1.60-1.85 (1H, m), 2.10-3.90 (7H, m), 4.25-4.55 (1H, m), 6.24 (1H,d, J=16 Hz), 6.55 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=16 Hz), 7.47 (1H, d,J=6.1 Hz), 7.77 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.19 (1H, d, J=2.1 Hz)

MASS(API-ES); 288 (M+H)+

Preparation 48

(2E)-3-(6-{[(3R)-1-Benzoyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.90-2.40 (2H, m), 3.20-4.00 (4H, m), 4.40-4.80 (1H,m), 6.30-6.50 (1H, m), 6.95-7.10 (1H, m), 7.35-7.60 (6H, m), 8.05-8.15(1H, m), 8.20-8.35 (1H, m), 12.26 (1H, br)

MASS(API-ES); 372 (M+H)+, 374

Preparation 49

(2E)-3-(5-Chloro-6-{[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 0.60-0.80 (4H, m), 1.60-1.85 (1H, m), 1.87-2.40 (2H,m), 3.20-4.10 (4H, m), 4.45-4.80 (1H, m), 6.42 (1H, d, J=16 Hz),6.90-7.05 (1H, m), 7.48 (1H, d, J=16 Hz), 8.07-8.14 (1H, m), 8.25-8.32(1H, m), 12.21 (1H, br)

MASS(API-ES, Nega); 334 (M−H)−

Preparation 50

(2E)-3-{6-[(1-Benzoyl-4-piperidyl)amino]-3-pyridyl}-acrylic acid

NMR (DMSO-d₆, δ): 1.20-1.60(2H, m), 1.70-2.10(2H, m), 3.00-3.60(3H, m),4.00-4.20(1H, m), 4.20-4.60(1H, m), 6.23(1H, d, J=16.0 Hz), 6.53(1H, d,J=8.8 Hz), 7.10-7.30(1H, m), 7.35-7.48(6H, m), 7.78(1H, dd, J=2.0, 8.8Hz), 8.19(1H, d, J=2.0 Hz)

Mass (APCI): 352(M+H)+

Preparation 51

(2E)-3-(6-{[1-(4-Fluorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.30-1.55(2H, m), 1.85-2.10(2H, m), 3.00-3.30(2H, m),3.58(1H, brs), 4.05-4.11(1H, m), 4.33(1H, brs), 6.22(H, d), 6.22(1H, d,J=8.4 Hz), 6.52(1H, d, J=8.8 Hz), 7.17(1H, brs), 7.26-7.30(2H, m),7.42-7.48(3H, m), 7.77(1H, dd, J=2.2, 8.8 Hz), 8.19(1H, d, J=2.2 Hz),12.06(1H, brs)

Mass (APCI): 392(M+Na)+

Preparation 52

(2E)-3-(6-{[1-(4-Methylbenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.20-1.60(2H, m), 1.80-2.10(2H, m), 2.34(3H, s),3.03-4.40(6H, m), 6.22(1H, d, J=16.0 Hz), 6.50(1H, d, J=8.8 Hz),7.14(1H, d, J=7.4 Hz), 7.21-7.31(4H, m), 7.44(1H, d, J=16.0 Hz),7.76(1H, dd, J=2.0, 8.8 Hz), 8.18(1H, d, J=2.0 Hz).

Mass (APCI): 383(M+Na)+

Preparation 53

(2E)-3-(6-{[1-(4-Methoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.31-1.16(2H, m), 1.80-2.00(2H, m), 3.00-3.20(2H, m),3.82(3H, s), 4.00-4.20(2H, m), 6.24(1H, d, J=16.0 Hz), 6.55(1H, d, J=8.8Hz), 6.99(2H, d, J=8.8 Hz), 7.27(1H, brs), 7.36(2H, d, J=8.8 Hz),7.44(1H, d, J=16.0 Hz), 7.78(1H, dd, J=2.1, 8.8 Hz), 8.19(1H, d, J=2.1Hz), 12.13(1H, brs)

Mass (APCI): 404(M+Na)+

Preparation 54

(2E)-3-[6-({1-[4-(1H-Pyrrol-1-yl)benzoyl]-4-piperidyl}-amino)-3-pyridyl]acrylicacid

NMR (DMSO-d₆, δ): 1.35-1.60(2H, m), 1.85-2.10(2H, m), 3.10-3.40(2H, m),3.50-4.50(3H, m), 6.28-6.33(3H, m), 6.54(1H, d, J=8.8 Hz), 7.23(1H, d,J=7.4 Hz), 7.42-7.50(6H, m), 7.66(2H, d, J=8.6 Hz), 7.77(1H, dd, J=2.0,8.8 Hz), 8.20(1H, d, J=2.0 Hz), 12.13(1H, brs)

Preparation 55

(2E)-3-(6-[(1-{[(4-Chlorophenyl)amino]carbonyl)-4-piperidyl)amino]-3-pyridyl}acrylicacid

NMR (DMSO-d₆, δ): 1.29-1.45(2H, m), 1.80-2.05(2H, m), 2.85-3.10(2H, m),3.80-4.20(3H, m), 6.25(1H, d, J=16.0 Hz), 6.75(1H, d, J=8.8 Hz),7.20-7.60(6H, m), 7.82(1H, dd, J=2.0, 8.8 Hz), 8.20d(1H, d, J=2.0 Hz),8.69(1H, s), 12.09(1H, brs).

Mass (APCI): 399(M−H)−

Preparation 56

(2E)-3-{6-[(1-{[(4-Methylphenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylicacid

NMR (DMSO-d₆, δ): 1.23-1.43(2H, m), 1.89-2.10(2H, m), 2.22(3H, s),2.84-3.01(2H, m), 4.02-7.10(3H, m), 6.23(1H, d, J=16.0 Hz), 6.52(1H, d,J=8.8 Hz), 7.02(2H, d, J=8.8 Hz), 7.18(1H, d, J=7.0 Hz), 7.34(2H, d,J=8.8 Hz), 7.45(1H, d, J=16.0 Hz), 7.76(1H, dd, J=2.0, 8.8 Hz), 8.20(1H,d, J=2.0 Hz), 8.43(1H, s), 12.04(1H, brs)

Mass (APCI): 403(M+Na)+

Preparation 57

(2E)-3-(6-[(1-{[(4-Methoxyphenyl)amino]carbonyl)-4-piperidyl)amino]-3-pyridyl}acrylicacid

NMR (DMSO-d₆, δ): 1.28-1.43(2H, m), 1.76-1.94(2H, m), 2.89-3.01(2H, m),3.70(3H, s), 4.01-4.08(3H, m), 6.23(1H, d, J=16.0 Hz), 6.52(1H, d, J=8.8Hz), 6.81(2H, d, J=8.8 Hz), 7.18-7.22(1H, m), 7.34(2H, d, J=8.8 Hz),7.45(1H, d, J=16.0 Hz), 7.77(1H, dd, J=2.0, 8.8 Hz), 8.20(1H, d, J=2.0Hz), 8.36(1H, s), 12.04(1H, brs)

Mass (APCI): 419(M+Na)+

Preparation 58

(2E)-3-{6-[(1-Benzoyl-4-piperidyl)amino]-5-chloro-3-pyridyl}acrylic acid

NMR (DMSO-d₆, δ): 1.50-2.01(4H, m), 2.60-3.80(4H, m), 4.2-4.7(2H, m),6.38(1H, d, J=16.0 Hz), 6.70(1H, d, J=8.0 Hz), 7.35-7.49(6H, m),8.08(1H, d, J=2.0 Hz), 8.26(1H, d, J=2.0 Hz)

Mass (APCI): 408(M+Na)+

Preparation 59

(2E)-3-(5-Chloro-6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.50-2.01(4H, m), 2.60-3.80(4H, m), 4.2-4.7(2H, m),6.38(1H, d, J=16.0 Hz), 6.70(1H, d, J=8.0 Hz), 7.35-7.57(5H, m),8.08(1H, d, J=2.0 Hz), 8.26(1H, d, J=2.0 Hz)

Mass (APCI): 442(M+Na)+

Preparation 60

(2E)-3-(5-Chloro-6-{[1-(4-phenoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.45-1.75(2H, m), 1.75-2.10(2H, m), 2.70-4.70(6H, m),6.37(1H, d, J=16.0 Hz), 6.61(1H, d, J=8.0 Hz), 7.07-7.47(9H, m),7.99(1H, s), 8.19(1H, s)

Mass (APCI): 476(M−H)−

Preparation 61

(2E)-3-(5-Chloro-6-{[1-(4-fluorobenzyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.80-2.20(4H, m), 2.90-3.24(2H, m), 4.10-4.40(3H, m),6.38(1H, d, J=16.0 Hz), 6.98(1H, d, J=7.8 Hz), 7.26-7.35(2H, m),7.46(1H, d, J=16.0 Hz), 7.67-7.73(2H, m), 8.09(1H, s), 8.23(1H, s),10.98(1H, brs), 12.21(1H, brs)

Preparation 62

A mixture of(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylic acid (400mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (159 mg), HOBt (175 mg)and EDCI (202 mg) in DMF (10 ml) was stirred at ambient temperature for15 hours. The reaction mixture was poured into a mixture of AcOEt-H₂Oand the organic layer was washed with brine and dried over MgSO₄. Thesolvent was evaporated in vacuo and the residue was chromatographed onsilicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containingthe desired product were collected and evaporated in vacuo to give(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(170 mg)

NMR (DMSO-d₆, δ): 1.52-1.68 (7H, m), 2.09-2.50 (3H, m), 2.61-2.81 (2H,m), 3.34 (2H, s), 3.34-3.57 (2H, m), 3.92-3.98 (1H, m), 4.32-4.33 (1H,m), 4.87 (1H, s), 6.20 (1H, d, J=15.20 Hz), 6.53 (1H, d, J=8.82 Hz),7.20-7.37 (7H, m), 7.58 (1H, d, J=7.90 Hz), 8.11 (1H d, J=1.84 Hz),11.03 (1H, brs)

The following compounds were obtained according to a similar manner tothat of Preparation 62.

Preparation 63

(2E)-3-(6-[(1-Benzyl-3-pyrrolidinyl)(methyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.17-1.76 (7H, m), 1.99-2.44 (2H, m), 2.49-3.00 (3H,m), 2.99 (3H, s), 3.49-3.69 (4H, m), 3.93-4.01 (1H, m), 4.89 (1H, s),5.29-5.33 (1H, m), 6.28 (1H, d, J=15.44 Hz), 6.69 (1H, d, J=9.02 Hz),7.19-7.42 (6H, m), 7.71 (1H, d, J=9.02 Hz), 8.24 (1H, s), 11.05 (1H, s)

Preparation 64

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.52-1.99 (7H, m), 2.22-2.50 (3H, m), 2.62-2.89 (2H,m), 3.57 (2H, s), 3.34-3.57 (2H, m), 3.98-4.05 (1H, m), 4.30 (1H, m),8.47 (1H, brs), 6.30 (1H, d, J=15.90 Hz), 6.52 (1H, d, J=8.80 Hz),7.20-7.37 (7H, m), 7.58 (1H, d, J=8.80 Hz), 8.11 (1H, s), 11.03 (1H, s)

Preparation 65

(2E)-3-(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.52-1.99 (7H, m), 2.22-2.45 (3H, m), 2.62-2.81 (2H,m), 3.51 (2H, s), 3.34-3.57 (2H, m), 3.92-4.00 (1H, m), 4.31 (1H, m),4.87 (1H, s), 6.20 (1H, d, J=16.10 Hz), 6.52 (1H, d, J=8.84 Hz),7.20-7.37 (7H, m), 7.58 (1H, d, J=7.76 Hz), 8.11 (1H, d, J=1.92 Hz),11.03 (1H, s)

Preparation 66

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.53-2.00 (7H, m), 2.00-2.30 (1H, m), 2.30-2.78 (3H,m), 2.82-2.89 (1H, m), 3.59 (2H, s), 3.36-3.59 (2H, m), 3.96-4.01 (1H,m), 4.41-4.55 (1H, m), 4.89 (1H, s), 6.32 (1H, d, J=15.68 Hz), 6.42 (1H,d, J=6.88 Hz), 7.19-7.40 (6H, m), 7.84 (1H, s), 8.20 (1H, s), 11.08 (1H,brs)

Preparation 67

(2E)-3-(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.53-2.00 (7H, m), 2.10-2.32 (1H, m), 2.39-2.53 (2H,m), 2.63-2.67 (1H, m), 2.74-2.89 (1H, m), 3.56 (2H, s), 3.50-3.59 (2H,m), 3.96-4.05 (1H, m), 4.48-4.53 (1H, m), 4.90 (1H, s), 6.33 (1H, d,J=15.74 Hz), 6.94 (1H, d, J=6.88 Hz), 7.19-7.33 (6H, m), 7.85 (1H, s),7.99 (1H, s), 8.20 (1H, s), 11.09 (1H, brs)

Preparation 68

(2E)-3-(6-{[(3R)-1-(4-Methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.40-1.80 (7H, m), 2.05-2.90 (5H, m), 3.40-3.60 (3H,m), 3.72 (3H, s), 3.80-4.05 (1H, m), 4.20-4.45 (1H, m), 4.87 (1H, s),6.20 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 6.86 (2H, d, J=8.5 Hz),7.21 (2H, d, J=8.5 Hz), 7.20-7.30 (1H, m), 7.33 (1H, d, J=16 Hz), 7.58(1H, dd, J=1.9 Hz, J=8.8 Hz), 8.11 (1H, d, J=1.9 Hz), 11.03 (1H, br)

MASS(API-ES); 453 (M+H)+

Preparation 69

(2E)-3-(6-{[(3R)-1-(4-Fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.45-1.80 (7H, m), 2.05-3.00 (5H, m), 3.20-3.65 (3H,m), 3.80-4.05 (1H, m), 4.20-4.45 (1H, m), 4.87 (1H, s), 6.20 (1H, d,J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.05-7.40 (6H, m), 7.59 (1H, dd, J=1.8Hz, J=8.8 Hz), 8.12 (1H, d, J=1.8 Hz), 11.05 (1H, br)

MASS(API-ES); 441 (M+H)+

Preparation 70

(2E)-3-(6-{[(3R)-1-(4-Chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.40-1.80 (7H, m), 2.05-2.90 (5H, m), 3.40-3.65 (3H,m), 3.80-4.05 (1H, m), 4.20-4.50 (1H, m), 4.87 (1H, s), 6.20 (1H, d,J=16 Hz), 6.52 (1H, d, J=8.8 Hz), 7.22 (1H, d, J=6.6 Hz), 7.27-7.45 (5H,m), 7.59 (1H, dd, J=1.9 Hz, J=8.8 Hz), 8.12 (1H, d, J=1.9 Hz), 11.04(1H, br)

MASS(API-ES); 457 (M+H)+459

Preparation 71

(2E)-3-(6-{[(3R)-1-(4-Methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.40-1.80 (7H, m), 2.05-2.85 (5H, m), 2.27 (3H, s),3.40-3.65(3H, m), 3.80-4.05 (1H, m), 4.20-4.45 (1H, m), 4.87 (1H, s),6.20 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.05-7.25 (5H, m), 7.33(1H, d, J=16 Hz), 7.58 (1H, dd, J=1.9 and 8.8 Hz), 8.11 (1H, d, J=1.9Hz), 11.03 (1H, br)

MASS(API-ES); 437 (M+H)+

Preparation 72

(2E)-3-(6-{[(3R)-1-(Cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 0.00-0.15 (2H, m), 0.35-0.50 (2H, m), 0.70-0.95 (1H,m), 1.40-1.85 (7H, m), 2.08-2.53 (5H, m), 2.55-2.82 (2H, m), 3.40-3.60(1H, m), 3.80-4.10 (1H, m), 4.20-4.50 (1H, m), 4.87 (1H, s), 6.21 (1H,d, 3=16 Hz), 6.52 (1H, d, J=8.8 Hz), 7.23 (1H, d, J=6.8 Hz), 7.34 (1H,d, J=16 Hz), 7.59 (1H, dd, J=1.9 and 8.8 Hz), 8.14 (1H, d, J=1.9 Hz),11.04 (1H, br)

MASS(API-ES); 387 (M+H)+

Preparation 73

(2E)-3-(6-{[(3R)-1-Benzoyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.40-1.80 (6H, m), 1.90-2.40 (2H, m), 3.10-4.10 (6H,m), 4.40-4.85 (1H, m), 4.89 (1H, s), 6.20-6.50 (1H, m), 6.90-7.05 (1H,m), 7.25-7.60 (6H, m), 7.80-7.95 (1H, m), 8.15-8.30 (1H, m), 11.10 (1H,br)

MASS(API-ES); 471 (M+H)+, 473

Preparation 74

(2E)-3-(5-Chloro-6-{[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 0.60-0.80 (4H, m), 1.40-1.85 (7H, m), 1.90-2.40 (2H,m), 3.15-4.10 (6H, m), 4.40-4.85 (1H, m), 4.89 (1H, s), 6.35 (1H, d,J=16 Hz), 6.85-7.00 (1H, m), 7.38 (1H, d, J=16 Hz), 7.88 (1H, s), 8.25(1H, s), 11.09 (1H, br)

MASS(API-ES); 435 (M+H)+, 437

Preparation 75

(2E)-3-(5-Chloro-6-{[1-(4-phenoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

Mass (APCI): 599(M+Na)+

Preparation 76

(2E)-3-(5-Chloro-6-{[1-(4-chlorobenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.45-1.90(9H, m), 1.95-2.15(2H, m), 2.70-2.82(2H, m),3.46(2H, s), 3.46-3.55(1H, m), 3.85-4.10(2H, m), 4.88(1H, s), 6.30(1H,d, J=16.0 Hz), 6.51(1H, d, J=7.0 Hz), 7.29-7.46(5H, m), 7.83(1H, s),8.20(1H, s), 11.08(1H, brs)

Preparation 77

(2E)-3-(5-Chloro-6-{[1-(4-fluorobenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.50-2.10(10H, m), 2.80-3.60(2H, m), 3.80-4.20(2H, m),4.88(1H, s), 6.32(1H, d, J=16.0 Hz), 6.80(1H, brs), 7.10-60(4H, m),7.36(1H, d, J=16.0 Hz), 7.86(1H, s), 8.20(1H, s), 11.09(1H, s),

Preparation 78

A mixture of methyl 6-chloronicotinate (8.0 g),(3R)-(−)-1-benzyl-3-aminopyrrolidine (9.86 g), CuO (371 mg) and K₂CO₃(8.38 g) in DMF (60 ml) was stirred at 100° C. for 10 hours underatmospheric pressure of nitrogen. The reaction mixture was poured into amixture of AcOEt and water and the organic layer was washed with brineand dried over MgSO₄. The solvent was evaporated in vacuo and theresidue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3).The eluted fractions containing the desired product were collected andevaporated in vacuo to give methyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}nicotinate (9.9 g).

NMR (DMSO-d₆, δ): 1.60-1.67 (1H, m), 2.19-2.36 (1H, m), 2.38-2.89 (2H,m), 2.62-2.81 (2H, m), 3.56 (2H, s), 3.58 (3H, s), 4.38 (1H, m), 6.51(1H, d, J=8.84 Hz), 7.18-7.33 (5H, m), 7.58 (1H, d, J=6.78 Hz), 8.00(1H, dd, J=2.22 Hz, 8.84 Hz), 8.55 (1H, d, J=2.22 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 78.

Preparation 79

Methyl 6-{[(3S)-1-benzyl-3-pyrrolidinyl]amino}nicotinate

NMR (DMSO-d₆, δ): 1.58-1.68 (1H, m), 2.17-2.24 (1H, m), 2.37-2.44 (2H,m), 2.62-2.82 (2H, m), 3.51 (2H, s), 3.76 (3H, s), 4.39 (1H, m), 6.53(1H, d, J=8.96 Hz), 7.19-7.33 (5H, m), 7.59 (1H, d, J=6.80 Hz), 7.81(1H, dd, J=2.20 Hz, 8.96 Hz), 8.56 (1H, d, J=2.20 Hz)

Preparation 80

A mixture of ethyl 5,6-dichloronicotinate (10.0 g),(3R)-(−)-1-benzyl-3-aminopyrrolidine (9.61 g), K₂CO₃ (8.38 g) and CuO(371 mg) in DMF (60 ml) was stirred at 100° C. for 10 hours underatmospheric pressure of nitrogen. The reaction mixture was poured into amixture of AcOEt and water and the organic layer was washed with brineand dried over MgSO₄. The solvent was evaporated in vacuo and theresidue was chromatographed on silicagel eluting with AcOEt-n-Hexane(7:3). The eluted fractions containing the desired product werecollected and evaporated in vacuo to give ethyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (15.95 g)

NMR (DMSO-d₆, δ): 1.29 (3H, t, J=7.08 Hz), 1.87-2.01 (1H, m), 2.17-2.21(1H, m), 2.41-2.53 (2H, m), 2.67-2.87 (2H, m), 3.59 (2H, s), 4.25 (2H,q, J=7.08 Hz), 4.54-4.59 (1H, m), 7.02 (1H, d, J=6.98 Hz), 7.19-7.33(5H, m), 7.92 (1H, d, J=1.96 Hz), 8.53 (1H, d, J=1.96 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 80.

Preparation 81

Ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.28 (3H, t, J=7.08 Hz), 1.87-1.96 (1H, m), 2.00-2.16(2H, m), 2.40-2.67 (3H, m), 2.80-2.87 (1H, m), 3.59 (2H, s), 4.25 (2H,q, J=7.08 Hz), 4.54-4.58 (1H, m), 7.03 (1H, d, J=6.98 Hz), 7.19-7.33(5H, m), 7.92 (1H, d, J=1.96 Hz), 8.53 (1H, d, J=1.96 Hz)

Preparation 82

A diisobutylaluminium hydride in toluene solution (15.7 ml) was dropwiseadded to a solution of ethyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (4.7 g) intoluene (50 ml) with stirring at −30˜−50° C. under atmospheric pressureof nitrogen, and the reaction mixture was stirred at −20˜−40° C. for 2hours. A MeOH (5 ml) was added to a reaction mixture at −40° C. andsaturated sodium potassium tartrate aqueous solution (10 ml) and MgSO₄(10 g) and the resultant mixture was stirred at ambient temperature for20 minutes. The reaction mixture was filtrated and the filtrate wasdried over MgSO₄. The solvent was evaporated in vacuo and the residuewas chromatographed on silicagel eluting with AcOEt-MeOH (9:1). Theeluted fractions containing the desired product were collected andevaporated in vacuo to give(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)methanol(1.87 g).

NMR (DMSO-d₆, δ): 1.77-1.99 (1H, m), 2.16-2.35 (1H, m), 2.36-2.52 (2H,m), 2.77-2.85 (2H, m), 3.58 (2H, s), 4.32 (2H, s), 4.42-4.49 (1H, m),5.10 (1H, m), 6.00 (1H, d, J=6.98 Hz), 7.18-7.32 (5H, m), 7.53 (1H, d,J=1.90 Hz), 7.91 (1H, d, J=1.90 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 82.

Preparation 83

(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.76-1.99 (1H, m), 2.08-2.33 (1H, m), 2.34-2.52 (2H,m), 2.62-2.76 (1H, m), 2.80-2.84 (1H, m), 3.57 (2H, s), 4.32 (2H, d,J=4.76 Hz), 4.41-4.45 (1H, m), 5.06 (1H, t, J=4.76 Hz), 6.03 (1H, d,J=6.96 Hz), 7.18-7.36 (5H, m), 7.53 (1H, d, J=1.94 Hz), 7.90 (1H, d,J=1.94 Hz)

Preparation 84

(5-Chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.70-1.89(1H, m), 2.15-2.29(1H, m), 2.34-2.86(4H, m),3.56(2H, s), 4.31(2H, d, J=5.5 Hz), 4.32-4.48(1H, m), 5.06(1H, t, J=5.5Hz), 6.04(1H, d, J=7.0 Hz), 7.08-7.34(4H, m), 7.54(1H, d, J=2.0 Hz),7.91(1H, d, J=2.0 Hz).

Mass (APCI): 336(M+H)+

Preparation 85

(5-Chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.72-1.85(1H, m), 2.08-2.85(5H, m), 2.27(3H, s),3.52(2H, s), 4.31(2H, d, J=5.5 Hz), 4.32-4.47(1H, m), 5.05(1H, t, J=5.5Hz), 6.02(1H, d, J=7.0 Hz), 7.10(2H, d, J=8.8 Hz), 7.18(2H, d, J=8.8Hz), 7.53(1H, d, J=2.0 Hz), 7.90(1H, d, J=2.0 Hz)

Mass (APCI): 332(M+H)+

Preparation 86

(5-Chloro-6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)methanol

Mass (ESI): 348(M+H)+

Preparation 87

A mixture of methyl 6-chloronicotinate (5.14 g),1-benzyl-4-aminopiperidine (6.84 g) and K₂CO₃ (5.38 g) in DMF (30 ml)was stirred at 100° C. for 12 hours under atmospheric pressure ofnitrogen. The reaction mixture was poured into a mixture of AcOEt andwater and the organic layer was washed with brine and dried over MgSO₄.The solvent was evaporated in vacuo and the residue was chromatographedon silicagel eluting with AcOEt-MeOH (98:2). The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.77 g)

NMR (DMSO-d₆, δ): 1.35-1.52 (2H, m), 1.84-1.89 (2H, m), 1.99-2.11 (2H,m), 1.73-2.81 (2H, m), 3.46 (2H, s), 3.75 (3H, s), 3.75-3.79 (1H, m),6.48 (1H, d, J=8.80 Hz), 7.19-7.36 (6H, m), 7.79 (1H, dd, J=2.28 Hz,8.80 Hz), 8.55 (1H, d, J=2.28 Hz)

Preparation 88

Lithium aluminium hydride (304 mg) was added to a solution of methyl6-[(1-benzyl-4-piperidyl)amino]nicotinate (1.3 g) in THF (20 ml) withstirring at 5-10° C. under atmospheric pressure of nitrogen, and thereaction mixture was stirred at 5-20° C. for 4 hours. The reactionmixture was cooled at 5° C. and water (0.3 ml), 15% NaOH solution (0.3ml) and water (0.9 ml) was added, the resultant mixture was stirred atambient temperature for 20 minutes. The reaction mixture was filtratedand the filtrate was dried over MgSO₄. The solvent was evaporated invacuo and the residue was chromatographed on silicagel eluting withAcOEt-MeOH (9:1). The eluted fractions containing the desired productwere collected and evaporated in vacuo to give{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl)methanol (670 mg)

NMR (DMSO-d₆, δ): 1.32-1.50 (2H, m), 1.84-1.89 (2H, m), 2.00-2.10 (2H,m), 2.74-2.80 (2H, m), 3.46-3.74 (1H, m), 3.41 (2H, s), 4.22 (2H, d,J=5.44 Hz), 4.87 (1H, t, J=5.44 Hz), 6.28 (1H, d, J=8.52 Hz), 6.42 (1H,d, J=8.52 Hz), 7.19-7.36 (6H, m), 7.85 (1H, s)

The following compound(s) were obtained according to a similar manner tothat of Preparation 88.

Preparation 89

(6-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)methanol

NMR (DMSO-d₆, δ): 1.42-1.49 (2H, m), 1.84-1.89 (2H, m), 2.00-2.11 (2H,m), 2.72-2.78 (2H, m), 3.63-3.73 (1H, m), 4.26 (2H, d, J=5.26 Hz), 4.86(1H, d, J=5.26 Hz), 6.28 (1H, d, J=7.60 Hz), 6.42 (1H, d, J=8.50 Hz),7.27-7.40 (5H, m), 7.85 (1H, d, J=2.08 Hz)

Preparation 90

4-{[5-(Hydroxymethyl)-2-pyridyl]amino}-N-phenyl-1-piperidinecarboxamide

NMR (DMSO-d₆, δ): 1.36-1.43 (2H, m), 1.89-1.94 (2H, m), 2.92-3.03 (2H,m), 3.90-4.08 (3H, m), 4.28 (2H, d, J=5.52 Hz), 4.88 (1H, t, J=5.52 Hz),6.37 (2H, m), 6.88-6.96 (1H, m), 7.18-7.36 (3H, m), 7.45 (1H, dd, J=2.02Hz, 8.38 Hz), 7.88 (1H, d, J=2.02 Hz), 8.50 (1H, s)

Preparation 91

A mixture of methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.2 g) inMeOH (50 ml) was hydrogenated over 10% palladium-carbon (1.5 g) under anatmospheric pressure of hydrogen at ambient temperature under stirringfor 15 hours. After removal of the catalyst and solvent was evaporatedin vacuo and the residue was triturated with AcOEt and IPE. Theprecipitate was collected by filtration to give methyl6-(4-piperidylamino)nicotinate (1.77 g).

NMR (DMSO-d₆, δ): 1.18-1.41 (2H, m), 1.81-1.87 (2H, m), 2.60-2.64 (2H,m), 2.99-3.14 (2H, m), 3.46 (3H, s), 3.46-3.76 (1H, m), 6.49 (1H, d,J=8.84 Hz), 7.28-7.39 (2H, m), 7.78 (1H, dd, J=2.26 Hz, 8.84 Hz), 8.55(1H, d, J=2.26 Hz)

Preparation 92

A mixture of {6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}methanol (670mg) and MnO₂ (2.94 g) in AcOEt (30 ml) was refluxed under stirring for 2hours. After removal of the insoluble material, and the solvent wasevaporated in vacuo to give6-[(1-benzyl-4-piperidyl)amino]nicotinaldehyde (560 mg)

NMR (DMSO-d₆, δ): 1.39-1.56 (2H, m), 1.86-1.91 (2H, m), 1.99-2.12 (2H,m), 2.76-2.82 (2H, m), 3.47 (2H, s), 3.87 (1H, m), 6.55 (1H, d, J=8.90Hz), 7.29-7.37 (5H, m), 7.65-7.74 (2H, m), 8.47 (1H, d, J=1.4 Hz), 9.65(1H, s)

The following compounds were obtained according to a similar manner tothat of Preparation 92.

Preparation 93

6-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}nicotinaldehyde

NMR (DMSO-d₆, δ): 1.37-1.56 (2H, m), 1.86-1.91 (2H, m), 2.02-2.13 (2H,m), 2.74-2.80 (2H, m), 3.86 (1H, m), 6.51 (1H, d, J=8.06 Hz), 7.30-7.41(3H, m), 7.92-7.96 (2H, m), 8.47 (1H, d, J=2.06 Hz), 9.65 (1H, s)

Preparation 94

4-[(5-Formyl-2-pyridyl)amino]-N-phenyl-1-piperidinecarboxamide

NMR (DMSO-d₆, δ): 1.31-1.50 (2H, m), 1.91-1.99 (2H, m), 2.94-3.05 (2H,m), 3.98-4.12 (3H, m), 6.75 (1H, d, J=8.86 Hz), 6.89-6.96 (1H, m),7.19-7.26 (2H, m), 7.44-7.49 (2H, m), 7.73-7.77 (2H, m), 8.50-8.54 (2H,m), 9.67 (1H, s)

Preparation 95

A solution of diethylphosphonoacetic acid ethyl ester (850 mg) in THF(10 ml) was added dropwise to a mixture of 60% sodium hydride in oil(167 mg) in THF (15 mL) with stirring at 10-20° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at ambienttemperature for 30 minutes. A solution of to the above mixture andresultant mixture was stirred at ambient temperature for 1.5 hour. Thereaction mixture was poured into a mixture of AcOEt-H₂O and the organiclayer was washed with brine and dried over MgSO₄. The solvent wasevaporated in vacuo and the residue was crystallized with IPE andn-hexane to give ethyl(2E)-3-(6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylate (450 mg).

NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.06 Hz), 1.36-1.53 (2H, m), 1.84-1.90(2H, m), 1.99-2.10 (2H, m), 2.75-2.81 (2H, m), 3.46 (2H, s), 3.75-3.79(1H, m), 4.15 (2H, q, J=7.06 Hz), 6.30 (1H, d, J=15.90 Hz), 6.49 (1H, d,J=8.86 Hz), 7.11 (1H, d=7.52 Hz), 7.19-7.37 (5H, m), 7.49 (1H, d,J=15.90 Hz), 7.76 (1H, dd, J=2.10 Hz, 8.86 Hz), 8.20 (1H, d, J=2.10 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 95.

Preparation 96

A solution of diethylphosphonoacetic acid ethyl ester (274 mg) in THF(10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (55mg) in THF (10 mL) with stirring at 10-20° C. under atmospheric pressureof nitrogen, and the reaction mixture was stirred at ambient temperaturefor 30 minutes. A solution of6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinaldehyde (210 mg) inTHF (10 ml) solution was added to the above mixture and resultantmixture was stirred at ambient temperature for 1.5 hour. The reactionmixture was poured into a mixture of AcOEt-H₂O and the organic layer waswashed with brine and dried over MgSO₄. The solvent was evaporated invacuo and the residue was chromatographed on silicagel eluting withAcOEt-MeOH (95:5). The eluted fractions containing the desired productwere collected and evaporated in vacuo to give ethyl(2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate(190 mg)

NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.06 Hz), 1.41-1.51 (2H, m), 1.84-1.90(2H, m), 2.01-2.11 (2H, m), 2.73-2.79 (2H, m), 3.78 (1H, m), 4.14 (2H,q, J=7.06 Hz), 6.30 (1H, d, J=15.86 Hz), 6.48 (1H, d, J=8.88 Hz), 7.11(1H, d, J=7.48 Hz), 7.30-7.41 (4H, m), 7.49 (1H, d, J=15.86 Hz), 7.76(1H, dd, J=2.04 Hz, 8.88 Hz), 8.19 (1H, d, J=2.04 Hz)

The following compounds were obtained according to a similar manner tothat of Preparation 96.

Preparation 97

Ethyl(2E)-3-(6-{[1-(anilinocarbonyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.06 Hz), 1.35-1.45 (2H, m), 1.90-1.95(2H, m), 2.92-3.05 (2H, m), 3.97-4.20 (4H, m), 6.32 (1H, d, J=15.90 Hz),6.51 (1H, d, J=8.80 Hz), 6.88-6.96 (1H, m), 7.17-7.26 (2H, m), 7.44-7.55(3H, m), 8.23 (1H, d, J=2.08 Hz), 8.53 (1H, s)

Preparation 98

A mixture of ethyl(2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylate (470 mg) and1N NaOH solution (2.6 ml) in MeOH (15 ml) was stirred at 65-70° C. for 2hours. The reaction mixture was evaporated in vacuo and the residue wasdissolved with AcOEt and H₂O. The aqueous solution was adjusted to PH6.0with aq.HCl and evaporated in vacuo. The residue was chromatographed onsilicagel eluting with AcOEt-MeOH (85:15). The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (430mg).

NMR (DMSO-d₆, δ): 1.91-2.13 (4H, m), 2.80-3.60 (2H, m), 3.39-3.49 (2H,m), 3.67 (2H, brs), 4.30-4.50 (1H, m), 6.27 (1H, d, J=15.85 Hz), 6.70(1H, m), 7.39-7.47 (4H, m), 7.67-7.79 (4H, m), 8.51 (1H, s)

Preparation 99

A mixture of methyl 6-(4-piperidylamino)nicotinate (1.0 g),4-chlorobenzoic acid (699 mg), HOBt (603 mg) and EDCI (693 mg) in DMF(20 ml) was stirred at ambient temperature for 15 hours. The reactionmixture was poured into a mixture of AcOEt-H₂O and the organic layer waswashed with brine and dried over MgSO₄. The solvent was evaporated invacuo and the residue was chromatographed on silicagel eluting withAcOEt-n-hexane (7:3). The eluted fractions containing the desiredproduct were collected and evaporated in vacuo to give methyl6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinate (1.21 g)

NMR (DMSO-d₆, δ): 1.42 (2H, m), 1.92-1.99 (2H, m), 2.94-3.34 (4H, m),3.76 (3H, s), 4.09-4.13 (1H, m), 6.52 (1H, d, J=8.84 Hz), 7.40-7.54 (5H,m), 7.81 (1H, dd, J=2.26 Hz, 8.84 Hz), 8.56 (1H, d, J=2.26 Hz)

Preparation 100

A mixture of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl)acrylicacid (430 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (157 mg), HOBt(181 mg) and EDCI (208 mg) in DMF (20 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof AcOEt-H₂O and the organic layer was washed with brine and dried overMgSO₄. The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with AcOEt-MeOH (9:1-8:2). Theeluted fractions containing the desired product were collected andevaporated in vacuo to give(2E)-3-(6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(180 mg).

NMR (DMSO-d₆, δ): 1.35-1.68 (8H, m), 1.84-1.90 (2H, m), 1.99-2.10 (2H,m), 2.73-2.89 (2H, m), 3.54 (2H, s), 3.73-3.79 (4H, m), 3.42-3.98 (1H,m), 4.87 (1H, s), 6.20 (1H, d, J=14.96 Hz), 6.50 (1H, d, J=8.82 Hz),7.00 (1H, d, J=7.54 Hz), 7.21-7.37 (6H, m), 7.58 (1H, d, J=8.82 Hz),8.12 (1H, s), 11.02 (1H, s)

The following compounds were obtained according to a similar manner tothat of Preparation 100.

Preparation 101

4-[(5-{(1E)-3-Oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-phenyl-1-piperidinecarboxamide

NMR (DMSO-d₆, δ): 1.29-1.68 (8H, m), 1.90-1.99 (2H, m), 2.89-3.04 (2H,m), 3.56-3.60 (1H, m), 3.95-4.10 (4H, m), 4.88 (1H, s), 6.22 (1H, d,J=15.18 Hz), 6.52 (1H, d, J=8.78 Hz), 6.86-6.96 (1H, m), 7.18-7.48 (5H,m), 7.59-8.15 (1H, m), 8.16 (1H, s), 8.51 (1H, s), 11.03 (1H, s)

Preparation 102

(2E)-3-(6-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.36-1.83 (10H, m), 1.90-2.12 (4H, m), 2.52-2.73 (2H,m), 3.54 (1H, m), 3.93 (1H, m), 4.87 (1H, brs), 6.12-6.22) 1H, m), 6.49(1H, d, J=8.82 Hz), 6.95-7.00 (1H, m), 7.30-7.41 (4H, m), 7.53-7.62 (1H,m), 8.12 (1H, s), 11.00 (1H, s)

Preparation 103

A mixture of methyl 6-(4-piperidylamino)nicotinate (0.73 g) and phenylisocyanate (388 mg) in THF (30 ml) was stirred at ambient temperaturefor 12 hours. IPE (30 ml) was added to a reaction mixture and theprecipitate was collected by filtration to give methyl6-{[1-(anilinocarbonyl)-4-piperidyl]amino}nicotinate (0.72 g)

NMR (DMSO-d₆, δ): 1.27-1.48 (2H, m), 1.90-1.95 (2H, m), 2.93-3.04 (2H,m), 3.77 (3H, s), 4.04-4.11 (3H, m), 6.51 (1H, d, J=8.88 Hz), 6.88-6.96(2H, m), 7.12-7.26 (2H, m), 7.40-7.49 (3H, m), 7.81 (1H, dd, J=8.88 Hz),8.53 (1H, s), 8.57 (1H, d, J=2.26 Hz)

Preparation 104

A mixture of ethyl(2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate(190 mg) and 1N NaOH solution (1.0 ml) in MeOH (20 ml) was stirred at70-75° C. for 2 hours. The reaction mixture was evaporated in vacuo andthe residue was dissolved in a mixture of AcOEt and water. The aqueoussolution was adjusted to PH4.5 and extract with AcOEt and THF. Theorganic layer was washed with brine and dried over MgSO₄. The solventwas concentrated in vacuo and the precipitate was collected byfiltration to give(2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid (85 mg)

NMR (DMSO-d₆, δ): 1.36-2.23 (6H, m), 2.92-3.03 (2H, m), 4.17 (1H, m),6.24 (1H, d, J=15.88 Hz), 6.54 (1H, d, J=7.94 Hz), 7.34-7.60 (4H, m),7.76 (1H, dd, J=1.82 Hz, 7.94 Hz), 8.18 (1H, d, J=1.82 Hz), 12.02 (1H,m)

The following compounds were obtained according to a similar manner tothat of Preparation 104.

Preparation 105

(2E)-3-(6-{[1-(Anilinocarbonyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.35-1.45 (2H, m), 1.91-1.95 (2H, m), 3.03-3.05 (2H,m), 3.96-4.10 (3H, m), 6.22 (1H, d, J=15.92 Hz), 6.51 (1H, d, J=8.80Hz), 6.88-6.96 (1H, m), 7.13-7.26 (3H, m), 7.41-7.49 (3H, m), 7.76 (1H,dd, J=2.08 Hz, 8.80 Hz), 8.19 (1H, d, J=2.08 Hz), 8.52 (1H, s), 12.05(1H, s)

Preparation 106

(2E)-3-(5-Chloro-6-{[1-(4-chlorobenzyl)-4-piperidyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.50-2.20(6H, m), 2.65-2.85(2H, m), 3.45(2H, s),4.88-4.22(1H, m), 6.37(1H, d, J=16.0 Hz), 6.49(1H, d, J=8.0 Hz),7.29-7.52(5H, m), 8.00(1H, d, J=2.0 Hz), 8.20(1H, d, J=2.0 Hz)

Preparation 107

To a solution of ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (4.74g) and 4-(Dimethylamino)pyridine (41.2 mg) in tetrahydrofuran (70 ml)was added di-tert-butyldicarbonate (5.89 g) at 20° C. and then stirredat 60° C. for 14 hours. The mixture was concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel (70 g) using a mixed solvent of dichloromethane and methanol(60:1 to 15:1). The fractions containing the objective compound werecollected and evaporated under reduced pressure. Ethyl(2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate(5.49 g) was obtained as colorless oil.

NMR (DMSO-d₆, δ): 1.27 (3H, t, J=6.8 Hz), 1.41 (9H, s), 1.80-2.20 (2H,m), 2.40-2.80 (4H, m), 3.44, 3.55 (2H, ABq, J=13 Hz), 4.21(2H, q, J=6.8Hz), 4.60-4.90 (1H, m), 6.78 (1H, d, J=16 Hz), 7.00-7.30 (5H, m), 7.34(1H, d, J=8.5 Hz), 7.71(1H, d, J=16 Hz), 8.20 (1H, dd, J=2.4 Hz, J=8.5Hz), 8.73 (1H, d, J=2.4 Hz),

MASS(API-ES); 452 (M+H)+.

Preparation 108

To a solution of ethyl(2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (5.45 g) in toluene (55 ml) was added1-chloroethyl chloroformate (2.59 g) at room temperature and stirred at20° C. for 1 hour. 1-Chloroethyl chloroformate (795 mg) andN,N-diisopropylethylamine (0.736 ml) was added to the mixture, and thesolution was stirred at 20° C. for 15 minutes. After it was concentratedunder reduced pressure, the resulting residue was dissolved in EtOH (70ml). The mixture was stirred at 65° C. for 30 minutes, and concentratedunder reduced pressure. The residue was poured into a mixture of aqNaHCO₃ solution (80 ml) and dichloromethane (100 ml). The organic layerwas separated and dried over sodium sulfate, and evaporated underreduced pressure to give crude oil. The oil was purified by columnchromatography (silica gel 125 g, dichloromethane/MeOH (60/1 to 15/1) togive ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylateas oil (2.0 g).

NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.1 Hz), 1.31-1.40 (9H, m), 1.60-2.10(2H, m), 2.30-3.20 (4H, m), 4.20 (2H, q, J=7.1 Hz), 4.50-4.80 (1H, m),6.76 (1H, d, J=16 Hz), 7.36 (1H, d, J 8.5 Hz), 7.6.8 (1H, d, J=16 Hz),8.19 (1H, dd, J=2.4 Hz, J=8.5 Hz), 8.72 (1H, d, J=2.4 Hz

MASS(API-ES); 362 (M+H)+

Preparation 109

To a mixture of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(350 mg) and 4-methoxybenzaldehyde (145 mg) in dichloromethane (5 ml)was added sodium triacetoxyborohydride (410 mg) at 20° C., and then itwas stirred at the same temperature for 18 hours. The reaction wasquenched with saturated aq NaHCO₃ solution, and the mixture wasextracted with dichloromethane. The organic layer was dried over sodiumsulfate, and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (11 g) using a mixed solvent ofdichloromethane and MeOH (100:1 to 35:1). The fractions containing theobjective compound were collected and evaporated under reduced pressure.ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(362 mg) was obtained as colorless syrup.

NMR (DMSO-d₆, δ): 1.27 (3H, t, J=7.1 Hz), 1.35 (9H, s), 1.80-2.20 (2H,m), 2.30-2.90 (4H, m), 3.36, 3.48 (2H, ABq, J=13 Hz), 3.71 (3H, s),4.21(H, q, J=7.1 Hz), 4.60-4.85 (1H, m), 6.78 (1H, d, J=16 Hz), 6.81(2H, d, J=8.6 Hz, 7.06 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=8.4 Hz),7.71(1H, d, J=16 Hz), 8.20 (1H, dd, J=2.4 Hz, J=8.4 Hz), 8.72 (1H, d,J=2.4 Hz)

MASS(API-ES); 482 (M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 109.

Preparation 110

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.27 (3H, t, J=7.1 Hz), 1.36 (9H, s), 1.80-2.20 (2H,m), 2.25-2.90 (4H, m), 3.42, 3.54 (2H, ABq, J=13 Hz), 4.21(2H, q, J=7.1Hz), 4.60-4.90 (1H, m), 6.78 (1H, d, J=16 Hz), 7.00-7.25 (4H, m), 7.34(1H, d, J=8.4 Hz), 7.71(1H, d, J 16 Hz), 8.20 (1H, dd, J=2.4 Hz, J=8.4Hz), 8.73 (1H, d, J=2.4 Hz)

MASS(API-ES); 470 (M+H)+

Preparation 111

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.27 (3H, t, J=7.1 Hz), 1.35 (9H, s), 1.85-2.25 (2H,m), 2.30-2.90 (4H, m), 3.42, 3.55 (2H, ABq, J=13 Hz), 4.22 (2H, q, J=7.1Hz), 4.60-4.90 (1H, m), 6.78 (1H, d, J=16 Hz), 7.17 (2H, d, J=8.4 Hz),7.31 (2H, d, J=8.4 Hz), 7.34 (1H, d, J=8.5 Hz), 7.71(1H, d, J=16 Hz),8.20 (1H, dd, J=2.3 and 8.5 Hz), 8.73 (1H, d, J=2.3 Hz)

MASS(API-ES); 486 (M+H)+488

Preparation 112

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.27 (3H, t, J=7.1 Hz, 1.35 (9H, s), 1.75-2.24 (2H,m), 2.26 (3H, s), 2.30-2.85 (4H, m), 3.38, 3.50 (2H, ABq, J=13 Hz), 4.21(2H, q, J=7.1 Hz), 4.60-4.85 (1H, m), 6.77 (1H, d, J=16 Hz), 6.95-7.10(4H, m), 7.33 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=16 Hz), 8.19 (1H, dd,J=2.4 Hz, J=8.4 Hz), 8.71 (1H, d, J=2.4 Hz)

MASS(API-ES); 466 (M+H)+

Preparation 113

To an ice-cooled solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(360 mg) in dichloromethane (2 ml) was added anisole (11.0 ml) and TFA(2.0 ml), the mixture was stirred at 20° C. for 1 hour. The mixedsolution was poured into a mixture of water (20 ml) and AcOEt (20 ml).The pH of the aqueous layer was adjusted to ca.9 with NaHCO₃. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and evaporated under reduced pressure to give ethyl(2E)-3-(6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylateas syrup (295 mg).

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.1 Hz), 1.60-2.00 (1H, m), 2.10-3.65(7H, m), 3.74 (3H, s), 4.15 (2H, q, J=7.1 Hz), 4.25-4.55 (1H, m), 6.35(1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz), 6.93 (2H, d, J=8.5 Hz),7.25-7.43 (3H, m), 7.51(1H, d, J=16 Hz), 7.82 (1H, dd, J=2.0 and 8.8Hz), 8.22 (1H, d, J=2.0 Hz)

MASS(API-ES); 382 (M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 113.

Preparation 114

Ethyl(2E)-3-(6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.1 Hz), 1.50-1.80 (1H, m), 2.10-2.90(5H, m), 3.58 (2H, br), 4.14 (2H, q, J=7.1 Hz), 4.20-4.50 (1H, m), 6.31(1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.05-7.40 (5H, m), 7.49 (1H,d, J=16 Hz), 7.78 (1H, dd, J=2.1 and 8.8 Hz), 8.20 (1H, d, J=2.1 Hz)

MASS(API-ES); 370 (M+H)+

Preparation 115

Ethyl(2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.1 Hz), 1.50-1.85 (1H, m), 2.10-3.00(5H, m), 3.20-3.90 (2H, m), 4.14 (2H, q, J=7.1 Hz), 4.20-4.50 (1H, m),6.32 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.30-7.45 (5H, m), 7.49(1H, d, J=16 Hz), 7.79 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.20 (1H, d, J=2.1Hz)

MASS(API-ES); 386 (M+H)+388

Preparation 116

Ethyl(2E)-3-(6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.1 Hz), 1.55-1.85 (1H, m), 2.10-3.10(5H, m), 2.29 (3H, s), 3.20-4.00 (2H, m), 4.14 (2H, q, J=7.1 Hz),4.25-4.50 (1H, m), 6.33 (1H, d, J=16 Hz), 6.52 (1H, d, J=8.8 Hz),7.10-7.30 (4H, m), 7.40 (1H, d, J=6.5 Hz), 7.50 (1H, d, J=16 Hz), 7.80(1H, dd, J=2.1 and 8.8 Hz), 8.21 (1H, d, J=2.1 Hz)

MASS(API-ES); 366 (M+H)+

Preparation 117

Ethyl(2E)-3-(6-{[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 0.00-0.20 (2H, m), 0.40-0.60 (2H, m), 0.75-1.00 (1H,m), 1.24 (3H, t, J=7.1 Hz), 1.55-1.80 (1H, m), 2.10-3.60 (7H, m), 4.15(2H, q, J=7.1 Hz), 4.25-4.50 (1H, m), 6.33 (1H, d, J=16 Hz), 6.53 (1H,d, J=8.8 Hz), 7.39 (1H, d, J=6.5 Hz), 7.51 (1H, d, J=16 Hz), 7.80 (1H,dd, J=2.2 Hz, J=8.8 Hz), 8.23 (1H, d, J=2.2 Hz)

MASS(API-ES); 316 (M+H)+

Preparation 118

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(310 mg) and cyclopropylmethyl bromide (116 mg) in acetonitrile (7 ml)was added potassium hydrogencarbonate (85.9 mg) and potassium iodide(28.5 mg) at 20 and then the mixture was stirred at 50° C. for 3 hours.The mixed solution was poured into a mixture of water (20 ml) and AcOEt(20 ml). The pH of the aqueous layer was adjusted to ca.9 with NaHCO₃.The organic layer was separated, washed with brine, dried over sodiumsulfate and evaporated under reduced pressure.

The resulting residue was purified by column chromatography on silicagel (8 g) using a mixed solvent of dichloromethane and MeOH (40:1 to20:1). The fractions containing the objective compound were collectedand evaporated under reduced pressure. Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(170 mg) was obtained as colorless syrup.

NMR (DMSO-d₆, δ): 0.00-0.10 (2H, m), 0.30-0.50 (2H, m), 0.65-0.90 (1H,m), 1.27 (3H, t, J=7.1 Hz), 1.39 (9H, s), 1.80-3.40 (8H, m), 4.21(2H, q,J=7.1 Hz), 4.60-4.90 (1H, m), 6.76 (1H, d, J=16 Hz), 7.37 (1H, d, J=8.5Hz), 7.69 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2.3 and 8.5 Hz), 8.73 (1H,d, J=2.3 Hz)

MASS(API-ES); 416 (M+H)+

Preparation 119

To a stirred suspension of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(430 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL)and the resulting mixture was stirred at ambient temperature for 2hours. The mixture was concentrated in vacuo. The residue was dissolvedin ethanol (5 mL) and to this solution was added 1N sodium hydroxideaqueous solution (50.1 mL) and the mixture was stirred at fifty degreefor 12 hours. The mixture was allowed to cool to ambient temperature. Tothe mixture was added concentrated hydrogen chloride in an ice bathuntil pH of the mixture became neutral. The mixture was concentrated invacuo. The mixture was dissolved in DMF (5 mL) and to the resultingsolution was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (129 mg),1-hydroxybenzotriazole (149 mg) and EDCI hydrochloride (211 mg). Afterstirring at ambient temperature for 2 hours, the mixture was cooled inan ice bath and to this was added saturated aqueous sodium bicarbonate(5 mL) and water (5 mL). The precipitate was filtered, washed with waterand dried to afford(2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(280 mg) as a pale tan solid.

NMR (DMSO-d₆, δ): 1.26 (9H, s), 1.42-1.78 (6H, m), 2.07-2.82 (6H, m),3.28-3.41 (1H, m), 3.49 (1H, d, J=13.9. Hz), 3.55 (1H, d, J=13.9 Hz),3.84-4.01 (1H, m), 4.24-4.39 (1H, m), 4.85 (1H, brs), 6.20 (1H, br.d,J=16.5 Hz), 6.50 (1H, d, J=8.6 Hz), 7.14-7.29 (1H, m), 7.22 (2H, d,J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.57 (1H, br.d, J=8.6 Hz), 8.09 (1H,brs)

MS (ES+) m/z 479.36

Preparation 120

tert-Butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl){(3R)-1-[4-(trifluoromethyl)benzyl]-3-pyrrolidinyl}carbamate

NMR (DMSO-d₆, δ): 1.35 (9H, s), 1.45-1.79 (6H, m), 1.87-2.23 (2H, m),2.44-2.67 (3H, m), 2.72-2.82 (1H, m), 3.48-3.59 (1H, m), 3.54 (1H, d,J=13.6 Hz), 3.65 (1H, d, J=13.6 Hz), 3.88-4.04 (1H, m), 4.68-4.83 (1H,m), 4.92 (1H, brs), 6.60 (1H, d, J=16.1 Hz), 7.35 (1H, d, J=8.1 Hz),7.39 (2H, d, J=8.4 Hz), 7.55 (1H, d, J=16.1 Hz), 7.63 (2H, d, J=8.4 Hz),8.02 (1H, br.d, J=8.1 Hz), 8.63 (1H, brs)

MS (ES+) m/z 591.28(M+1).

Preparation 121

tert-Butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl){(3R)-1-[4-(trifluoromethoxy)benzyl]-3-pyrrolidinyl}carbamate

NMR (DMSO-d₆, δ): 1.35 (9H, s), 1.46-1.81 (6H, m), 1.86-2.20 (2H, m),2.45-2.65 (3H, m), 2.71-2.81 (1H, m), 3.43-3.65 (3H, m); 3.90-4.06 (1H,m), 4.66-4.84 (1H, m), 4.92 (1H, brs), 6.59 (1H, d, J=15.8 Hz), 7.25(2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=8.1 Hz), 7.55(1H, d, J=15.8 Hz), 8.02 (1H, brd, J=8.1 Hz), 8.63 (1H, brs)

MS (ES+) m/z 607.29(M+1)

Preparation 122

tert-Butyl[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl)-2-pyridyl)carbamate

NMR (DMSO-d₆, δ): 0.59-1.77 (17H, m), 1.37 (9H, s), 1.85-2.22 (4H, m),2.23-2.78 (4H, m), 3.47-3.59 (1H, m), 3.88-4.04 (1H, m), 4.64-4.84 (1H,m), 4.92 (1H, brs), 6.58 (1H, d, J=16.5 Hz), 7.35 (1H, d, J=8.1 Hz),7.53 (1H, d, J=16.5 Hz), 8.01 (1H, br.d, J=8.1 Hz), 8.63 (1H, brs)

MS (ES+) m/z 529.44(M+1)

Preparation 123

tert-Butyl[(3R)-1-(1-cyclohexen-1-ylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (DMSO-d₆, δ): 1.14-2.20 (16H, m), 1.36 (9H, s), 2.33-2.50 (3H, m),2.56-2.73 (2H, m), 2.78-2.88 (1H, m), 3.49-3.61 (1H, m), 3.90-4.04 (1H,m), 4.64-4.79 (1H, m), 4.92 (1H, brs), 5.43 (1H, brs), 6.58 (1H, d,J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=16.1 Hz), 8.00 (1H,br.d, J=8.4 Hz), 8.63 (1H, brs)

MS (ES+) m/z 527.54(M+1)

Preparation 124

The mixture of 1-chloro-3-(triphenylphosphoranylidene)acetone (6.6 g)and ethyl glyoxylate (50% in toluene, 4.6 g) in dioxane (66 mL) wasstirred at 80′ for 1.5 hour. The solvent was removed by concentration.The residue was purified by column chromatography on silica gel using amixture of chloroform and hexane (1:1 v/v) as an eluent. The elutedfractions containing the desired product were collected and evaporatedin vacuo to give ethyl (2E)-5-chloro-4-oxo-2-pentenoate (1.58 g).

NMR(DMSO-d₆, δ): 1.25(3H, t, J=7.1 Hz), 4.22(2H, q, J=7.1 Hz), 4.85(2H,s), 6.78(1H, d, J=16.1 Hz), 7.07(1H, d, J=16.1 Hz)

Preparation 125

The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.5 g) andN-[1-(4-chlorobenzoyl)-3-pyrrolidinyl]thiourea (0.8 g) in acetonitrile(10 mL) was stirred at 70° C. for 3 hours, and the mixture wasevaporated in vacuo. To the residue was added a solution of AcOEt andwater, and the mixture was adjusted to pH 8 with 20% aqueous potassiumcarbonate. The separated organic layer was washed with water, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel using AcOEt as an eluent. The elutedfractions containing the desired product were collected and evaporatedin vacuo to give ethyl(2E)-3-(2-([1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate(1.0 g).

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.1 Hz), 1.88-2.28(2H, m), 3.29-3.72(3H,m), 3.74-3.87(1H, m), 4.07-4.40(3H, m), 6.27 and 6.49(total 1H, each d,J=15.3 Hz), 7.16 and 7.21(total 1H, each s), 7.31 and 7.37(total 1H,each d, J=15.3 Hz), 7.44-7.62(4H, m), 8.07 and 8.11 (total 1H, each d,J=6.0 Hz)

(+)ESI-MS: 406(M+H)+, 428(M+Na)+

The following compounds were obtained according to a similar manner tothat of Preparation 125.

Preparation 126

Ethyl (2E)-3-{2-[(1-benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl)acrylate

NMR(DMSO-d₆, δ): 1.23(3H, t, J=7.1 Hz), 1.35-1.58(2H, m), 1.85-2.16(4H,m), 2.68-2.83(2H, m), 3.42-3.62(1H, m), 3.46(2H, s), 4.15(2H, q, J=7.1Hz), 6.32(1H, d, J=15.2 Hz), 7.12(1H, s), 7.20-7.37(6H, m), 7.76(1H, d,J=7.1 Hz)

(+)ESI-MS: 372(M+H)+

Preparation 127

The mixture of ethyl(2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate(0.9 g) and 1N-NaOH (4.4 mL) in MeOH (14 mL) was stirred at 50° C. for 3hours and the mixture was evaporated in vacuo. To the residue was addeda solution of AcOEt, THF and water, and the mixture was adjusted to pH 4with 1N-HCl. The separated organic layer was washed with water, driedover magnesium sulfate and evaporated in vacuo to give(2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylicacid (0.64 g).

NMR(DMSO-d₆, δ): 1.84-2.32(2total 1H, m), 3.27-3.71(3H, m),3.72-3.88(1H, m), 4.20-4.40(1H, m), 6.24 and 6.34(total 1H, each d,J=15.3 Hz), 7.11 and 7.16(total 1H, each s), 7.25 and 7.31(total 1H,each d, J=15.3 Hz), 7.45-7.62(4H, m), 8.02-8.15(1H, m), 12.27(1H, s)

(+)ESI-MS: 400(M+Na)+

The following compounds were obtained according to a similar manner tothat of Preparation 127.

Preparation 128

(2E)-3-{2-[(1-Benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl}acrylic acid

NMR(DMSO-d₆, δ): 1.38-1.60(2H, m), 1.87-2.04(2H, m), 2.04-2.26(2H, m),2.72-2.87(2H, m), 3.46-3.63(3H, m), 6.27(1H, d, J=15.1 Hz), 7.07(1H, s),7.20-7.36(6H, m), 7.77(1H, d, J=7.2 Hz)

Preparation 129

(2E)-3-(2-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)acrylicacid

NMR(DMSO-d₆, δ): 1.31-1.56(2H, m), 1.88-2.13(2H, m), 3.05-3.29(2H, m),3.46-3.67(1H, m), 3.75-3.93(1H, m), 4.14-4.36(1H, m), 6.29(1H, d, J=15.3Hz), 7.10(1H, s), 7.27(1H, d, J=15.3 Hz), 7.42(2H, d, J=8.5 Hz),7.52(2H, d, J=8.5 Hz), 7.84(1H, d, J=6.9 Hz), 12.26(1H, s)

(+)ESI-MS: 414(M+Na)+

Preparation 130

EDCI (0.30 g) was added to the solution of(2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylic-acid(0.6 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.22 g), and HOBT(0.26 g) in DMF (10 ml) under ice-cooling and the mixture was stirred atambient temperature for 20 hours. The reaction mixture was poured into amixture of AcOEt and water. The separated organic layer was washed withwater, dried over magnesium sulfate and evaporated in vacuo to give(2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(0.66 g).

NMR(DMSO-d₆, δ): 1.44-1.75(6H, m), 1.90-2.29(2H, m), 3.27-3.68(4H, m),3.69-4.05(2H, m), 4.20-4.38(1H, m), 4.85-4.94(1H, m), 6.39 and6.47(total 1H, each d, J=15.2 Hz), 7.01 and 7.06(total 1H, each s), 7.16and 7.21(total 1H, each d, J=15.2 Hz), 7.46-7.61(4H, m), 7.99-8.08(1H,m), 11.18 and 11.24(total 1H, each s)

(+)ESI-MS: 477(M+H)+, 499(M+Na)+

The following compounds were obtained according to a similar manner tothat of Preparation 130.

Preparation 131

(2E)-3-{2-[(1-Benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR(DMSO-d₆, δ): 1.39-1.76(8H, m), 1.85-2.20(4H, m), 2.68-2.84(2H, m),3.42-3.64(2H, m), 3.47(2H, s), 3.86-4.02(1H, m), 4.85-4.92(1H, m),6.40(1H, d, J=15.1 Hz), 6.96(1H, s), 7.17(1H, d, J=15.1 Hz),7.22-7.35(5H, m), 7.68(1H, d, J=7.2 Hz), 11.20(1H, s)

(+)ESI-MS: 443(M+H)+

Preparation 132

(2E)-3-(2-([1-(4-Chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR(DMSO-d₆, δ): 1.33-1.76(8H, m), 1.89-2.11(2H, m), 3.05-3.26(2H, m),3.44-3.64(2H, m), 3.74-4.02(2H, m), 4.14-4.35(1H, m), 4.84-4.92(1H, m),6.41(1H, d, J=15.1 Hz), 7.00(1H, s), 7.18(1H, d, J=15.1 Hz), 7.42(2H, d,J=8.5 Hz), 7.53(2H, d, J=8.5 Hz), 7.79(1H, d, J=7.2 Hz), 11.21(1H, s)

Preparation 133

1-Chloroethyl chloroformate (1.88 mL) was added a mixture of ethyl(2E)-3-(2-[(1-benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl)acrylate (2.7g) in dichloromethane (40 mL) at ambient temperature and the mixture wasstirred at same temperature for 1.5 hour. The solvent was removed byconcentration. To the residue was added an EtOH (42.7 mL) and themixture was stirred at 70° C. for 2 hours. The reaction mixture wasadded 2N-ethanolic hydrogen chloride (7.3 mL) at ambient temperature andthe mixture was stirred at same temperature for 20 hours. The isolatedprecipitate was collected by filtration to give ethyl(2E)-3-[2-(4-piperidylamino)-1,3-thiazol-4-yl]acrylate dihydrochloride(1.44 g).

NMR(DMSO-d₆, δ): 1.24(3H, t, J=7.1 Hz), 1.66-1.88(2H, m), 2.04-2.21(2H,m), 2.88-3.11(2H, m), 3.21-3.38(2H, m), 4.05-4.24(1H, m), 4.17(2H, q,J=7.1 Hz), 6.67(1H, d, J=15.6 Hz), 7.32(1H, s), 7.61(1H, d, J=15.6 Hz),9.14(4H, br s)

(+)ESI-MS: 282(M+H)+

Preparation 134

4-Chlorobenzoyl chloride (0.19 mL) was added to a mixture of ethyl(2E)-3-[2-(4-piperidylamino)-1,3-thiazol-4-yl]acrylate dihydrochloride(0.5 g) and triethylamine (0.63 mL) in DMF (10 ml) under ice-cooling andthe mixture was stirred at same temperature for 4.5 hours. The reactionmixture was poured into saturated aqueous sodium hydrogen carbonate andthe mixture was extracted with an AcOEt. The extract layer was washedwith water, dried over magnesium sulfate and evaporated in vacuo to giveethyl(2E)-3-(2-([1-(4-chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)acrylate(0.48 g).

NMR(DMSO-d₆, δ): 1.24(3H, t, J=7.1 Hz), 1.32-1.56(2H, m), 1.87-2.13(2H,m), 3.05-3.29(2H, m), 3.44-3.65(1H, m), 3.76-3.95(1H, m), 4.07-4.35(1H,m), 4.15(2H, q, J=7.1 Hz), 6.34(1H, d, J=15.2 Hz), 7.16(1H, s), 7.34(1H,d, J=15.2 Hz), 7.42(2H, d, J=8.5 Hz), 7.52(2H, d, J=8.5 Hz), 7.86(1H, d,J=7.0 Hz)

(+)ESI-MS: 442(M+Na)+

Preparation 135

To a solution of ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate(770 mg) in toluene (14 ml) was added 1-chloroethyl chloroformate (713mg) at 23° C. and stirred at the same temperature for 1 hour.N,N-Diisopropylethylamine (0.348 ml) was added to the mixture, and thesolution was stirred at 23° C. for 15 minutes. After it was concentratedunder reduced pressure, the resulting residue was dissolved in EtOH (15ml). The mixture was stirred at 65° C. for 30 minutes, and concentratedunder reduced pressure. The residue was dissolved into EtOH (15 ml), andmixed with 2N-hydrogen chloride in EtOH solution (2 ml). The mixture wasstirred at 86° C. for 5 hours. After it was concentrated under reducedpressure, the resulting residue was triturated with IPE (15 ml). Ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylatedihydrochloride (1.1 g) was obtained as brown syrup.

NMR (DMSO-d₆, δ): 1.29 (3H, t, J=6.9 Hz), 1.90-2.35 (2H, m), 3.00-4.10(4H, m), 4.17 (2H, q, J=6.9 Hz), 4.30-4.85 (1H, m), 6.55 (1H, d, J=16Hz), 7.55 (1H, d, J=16 Hz), 8.15-8.20 (1H, m), 8.30-8.40 (1H, m), 9.56(4H, br)

MASS(API-ES); 296 (M+H)+Free, 298

Preparation 136

To an ice-cooled solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylatedihydrochloride (330 mg) and Et₃N (0.437 ml) in dichloromethane (8 ml)was added benzoyl chloride (132 mg), the mixture was stirred at 23° C.for 1 hour. The mixed solution was poured into a mixture of water (20ml) and DCM (15 ml). The organic layer was separated, washed with brine,dried over sodium sulfate and evaporated under reduced pressure. Theresulting residue was purified by column chromatography on silica gel(12 g) using a mixed solvent of dichloromethane and MeOH (100:1 to40:1). The fractions containing the objective compound were collectedand evaporated under reduced pressure. ethyl(2E)-3-(6-{[(3R)-1-benzoyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate(245 mg) was obtained as colorless syrup.

NMR (DMSO-d₆, δ): 1.18-1.32 (3H, m), 1.90-2.40 (2H, m), 3.20-4.10 (4H,m), 4.11-4.25 (2H, m), 4.40-4.80 (1H, m), 6.40-6.60 (1H, m), 7.00-7.15(1H, m), 7.35-7.65 (6H, m), 8.10-8.20 (1H, m), 8.22-8.40 (1H, m)

MASS(API-ES); 400 (M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 136.

Preparation 137

Ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 0.60-0.80 (4H, m), 1.24 (3H, t, J=7.1 Hz), 1.60-1.85(1H, m), 1.87-2.40 (2H, m), 3.20-4.10 (4H, m), 4.16 (2H, q, J=7.1 Hz),4.40-4.80 (1H, m), 6.52 (1H, d, J=16 Hz), 6.95-7.10 (1H, m), 7.53 (1H,d, J=16 Hz), 8.10-8.20 (1H, m), 8.30-8.40 (1H, m)

MASS(API-ES); 364 (M+H)+

Preparation 138

To a stirred solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(330 mg) in dimethylformamide (6 mL) was added potassium carbonate (158mg) and 1,1′-(bromomethylene)dibenzene (225 mg), and the mixture wasstirred at 60° C. for 2 hours. The resulting mixture was poured intowater and extracted with ethyl acetate. The organic phase was washedwith brine, dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified by chromatography (hexane:ethyl acetate=4:1 thenchloroform:methanol=20:1) to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(210 mg) as an oil.

NMR (DMSO-d₆, δ): 1.36 (3H, t, J=7 Hz), 1.42 (3×3H, s), 2.02-2.30 (2H,m), 2.42-2.61 (2H, m), 2.64 (1H, dd, J=9.5, 7 Hz), 2.78 (1H, dd, J=9.5,8 Hz), 4.17 (1H, s), 4.29 (2H, q, J=7 Hz), 4.91 (1H, m), 6.49 (1H, d,J=16 Hz), 7.08-7.38 (11H, m), 7.69 (1H, d, J=16 Hz), 7.83 (1H, dd,J=8.5, 2 Hz), 8.57 (1H, d, J=2 Hz)

MS (ES+) m/z 528.

Preparation 139

To a stirred solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(205 mg) in methanol (5 mL) was added 1N-NaOH solution (0.8 mL). Themixture was stirred at ambient temperature for 12 hours. Methanol wasevaporated in vacuo and the aqueous layer was washed with diisopropylether. The aqueous layer was acidified by hydrochloric acid to pH 4, andthe precipitate was collected and washed with water to give(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid (161 mg) as a white powder.

NMR (DMSO-d₆, δ): 1.34 (3×3H, br-s), 1.97-2.74 (6H, m), 4.17 (1H, br),4.75 (1H, br), 6.70 (1H, br-d, J=16 Hz), 7.12-7.90 (12H, m), 8.23 (1H,m), 8.76 (1H, s)

MS (ES+) m/z 500

Preparation 140

To a stirred solution of(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid (142 mg) in DMF (3 mL) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (67 mg), HOBT (77 mg), andEDCI hydrochloride (109 mg), and the resulting mixture was stirred atambient temperature for 7 hours. The reaction mixture was diluted withethyl acetate and washed successively with water, saturated NaHCO₃solution, and brine. The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by preparative thinlayer chromatography (chloroform:methanol=5:1) to give tert-butyl[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate(100 mg) as a pale yellow oil.

NMR (DMSO-d₆, δ): 1.34 (3×3H, s), 1.46-1.76 (6H, m), 1.93-2.21 (2H, m),2.25-2.64 (4H, m), 3.54 (1H, m), 3.97 (1H, m), 4.17 (1H, s), 4.75 (1H,m), 4.93 (1H, m), 6.64 (1H, d, J=16 Hz), 7.07-7.43 (11H, m), 7.59 (1H,d, J=16 Hz), 8.08 (1H, m), 8.68 (1H, d, J=1.5 Hz), 11.34 (1H, s)

MS (ES+) m/z 599.

Preparation 141

To a mixture of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylatedihydrochloride (150 mg), [4-(bromomethyl)phenyl](phenyl)methanone (143mg), and THF (3.5 mL) was added Et₃N (0.168 mL). After stirring for 2hours at room temperature, the reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover MgSO₄, filtered, and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel to give ethyl(2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate(149 mg)

NMR (CDCl₃, δ): 1.35 (3H, t, J=7 Hz), 1.45 (9H, s), 2.03-2.32 (2H, m),2.61-3.05 (4H, m), 3.61-3.76 (2H, m), 4.28 (2H, q, J=7 Hz), 4.87-5.00(1H, m), 6.46 (1H, d, J=16 Hz), 7.30 (1H, d, J=8 Hz), 7.37 (2H, d, J=8Hz), 7.45-7.51 (2H, m), 7.56-7.62 (1H, m), 7.66 (1H, d, J=16 Hz), 7.74(2H, d, J=8 Hz), 7.77-7.83 (3H, m), 8.54 (1H, d, J=2 Hz)

MS (ES+) m/z 556 (M+1)

Preparation 142

To a mixture of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylatedihydrochloride (110 mg), 4-(chloromethyl)-2-phenyl-1,3-thiazole (53.1mg), and DMF (2.5 mL) was added K₂CO₃ (123 mg). After stirring for 2hours at 60° C., the reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with brine, dried overMgSO₄, filtered, and evaporated in vacuo to give ethyl(2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate(133 mg).

NMR (DMSO-d₆, δ): 1.35 (3H, t, J=7 Hz), 1.44 (9H, s), 2.01-2.36 (2H, m),2.70-3.16 (4H, m), 3.77-3.92 (2H, m), 4.28 (2H, q, J=7 Hz), 4.90-5.01(1H, m), 6.42 (1H, d, J=16 Hz), 7.07 (1H, s), 7.31 (1H, d, J=8 Hz),7.40-7.45 (3H, m), 7.62 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 8 Hz),7.91-7.95 (2H, m), 8.51 (1H, d, J=2 Hz)

MS (ES+) m/z 535 (M+1)

Preparation 143

To a mixture of 2,3-dihydro-1-benzofuran-5-ylmethanol (95.1 mg), Et₃N(0.120 mL), and THF (3 mL) was added methanesulfonyl chloride (0.053 mL)at 4° C. The reaction mixture was stirred for 3 hours, and added ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylatedihydrochloride (250 mg) and Et₃N (0.281 mL). After stirring for 2 hoursat 60° C., the resulting mixture was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over MgSO₄,filtered, and evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(134 mg)

NMR (CDCl₃, δ): 1.35 (3H, t, J=7 Hz), 1.44 (9H, s), 1.98-2.27 (2H, m),2.51-3.00 (4H, m), 3.16 (2H, t, J=9 Hz), 3.44-3.57 (2H, m), 4.28 (2H, q,J=7 Hz), 4.55 (2H, t, J=9 Hz), 4.83-4.96 (1H, m), 6.46 (1H, d, J=16 Hz),6.68 (1H, d, J=8 Hz), 6.95 (1H, d, J=8 Hz), 7.08 (1H, s), 7.29 (1H, d,J=8 Hz), 7.66 (1H, d, J=16 Hz), 7.80 (1H, dd, J=2, 8 Hz), 8.53 (1H, d,J=2 Hz)

MS (ES+) m/z 494 (M+1)

Preparation 144

To a solution of ethyl(2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate(111 mg) in dioxane (2 mL) was added 1N sodium hydroxide (0.6 mL). Afterstirring at 60° C. for 2 hours, the reaction mixture was added H₂O (10mL) and acidified with 1N hydrochloric acid (to pH 1). A resultingmixture was extracted with CHCl₃, and the organic layer was dried overMgSO₄, filtered, and evaporated in vacuo to give(2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylicacid dihydrochloride (97 mg).

NMR (DMSO-d₆, δ): 1.46 (9H, s), 2.37-2.77 (2H, m), 3.51-3.99 (4H, m),4.38-4.47 (2H, m), 5.12-5.24 (1H, m), 6.41 (1H, d, J=16 Hz), 7.30 (1H,d, J=8 Hz), 7.47-7.65 (4H, m), 7.78-7.90 (7H, m), 8.42-8.49 (1H, m)

MS (ES+) m/z 528 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 144.

Preparation 145

(2E)-3-[6-((tert-Butoxycarbonyl){(3R)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylicacid dihydrochloride

NMR (CDCl₃, δ): 1.44 (9H, s), 2.28-2.68 (2H, m), 3.47-4.00 (4H, m),4.51-4.56 (2H, m), 5.18-5.32 (1H, m), 6.38 (1H, d, J=16 Hz), 7.33 (1H,d, J=8 Hz), 7.42-7.48 (3H, m), 7.52 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2and 8 Hz), 7.89-7.96 (3H, m), 8.42-8.47 (1H, m)

MS (ES+) m/z 507 (M+1)

Preparation 146

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid dihydrochloride

NMR (DMSO-d₆, δ): 1.46 (9H, s), 2.27-2.79 (2H, m), 3.24 (2H, t, J=9 Hz),3.39-3.94 (4H, m), 4.20-4.26 (2H, m), 4.60 (2H, t, J=9 Hz), 5.08-5.21(1H, m), 6.40 (1H, d, J=16 Hz), 6.79 (1H, d, J=8 Hz), 7.22-7.33 (2H, m),7.54-7.64 (2H, m), 7.77-7.82 (1H, m), 8.39-8.42 (1H, m)

MS (ES+) m/z 466 (M+1)

Preparation 147

(2E)-3-[(6-[[(3R)-1-(1-Benzofuran-2-ylmethyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl)acrylicacid dihydrochloride

NMR (DMSO-d₆, δ): 1.41 (9H, s), 2.25-2.71 (2H, m), 3.44-4.00 (4H, m),4.50-4.56 (2H, m), 5.16-5.30 (1H, m), 6.36 (1H, d, J=16 Hz), 7.16 (1H,s), 7.29-70.40 (3H, m), 7.47-7.65 (3H, m), 7.77 (1H, dd, J 2, 8 Hz),8.14-8.35 (1H, m)

MS (ES+) m/z 464 (M+1).

Preparation 148

(2E)-3-{6-[[(3R)-1-(1-Benzofuran-5-ylmethyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylicacid dihydrochloride

NMR (DMSO-d₆, δ): 1.45 (9H, s), 2.33-2.76 (2H, m), 3.39-3.99 (4H, m),4.37-4.50 (2H, m), 5.09-5.23 (1H, m), 6.39 (1H, d, J=16 Hz), 6.82 (1H,d, J=2 Hz), 7.30 (1H, d, J=8 Hz), 7.50-7.62 (3H, m), 7.68 (1H, d, J=2Hz), 7.78 (1H, dd, J=2, 8 Hz), 7.95 (1H, s), 8.30-8.44 (1H, m)

MS (ES+) m/z 464 (M+1)

Preparation 149

To a mixture of(2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylicacid dihydrochloride (93 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine(27 mg.), and 1-hydroxybenzotriazole (31 mg) in N,N-dimethylformamide(1.6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (36 mg)at 4° C. The mixture was warmed to ambient temperature and stirred for 8hours. The reaction mixture was added saturated NaHCO₃ (2 mL) and water(8 mL), and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over MgSO₄, filtered, and evaporated invacuo. The residue was purified by column chromatography on silica gelto give tert-butyl[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate(35 mg)

NMR (DMSO-d₆, δ): 1.36 (9H, s), 1.49-1.72 (6H, m), 1.88-2.20 (2H, m),2.50-2.86 (4H, m), 3.50-3.70 (3H, m), 3.89-4.02 (1H, m), 4.70-4.83 (1H,m), 4.90-4.94 (1H, m), 6.59 (1H, d, J=16 Hz), 7.33-8.05 (12H, m),8.62-8.65 (1H, m).

MS (ES+) m/z 627 (M+1).

The following compounds were obtained according to a similar manner tothat of Preparation 149.

Preparation 150

tert-Butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl){(3R)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}carbamate

NMR (DMSO-d₆, δ): 1.35 (9H, s), 1.49-1.75 (6H, m), 1.88-2.18 (2H, m),2.52-2.99 (4H, m), 3.50-3.59 (1H, m), 3.65-3.79 (2H, m), 3.91-4.03 (1H,m), 4.68-4.81 (1H, m), 4.90-4.96 (1H, m), 6.56 (1H, d, J=16 Hz),7.33-7.55 (6H, m), 7.87-8.02 (3H, m), 8.58-8.62 (1H, m).

MS (ES+) m/z 606 (M+1).

Preparation 151

tert-Butyl[(3R)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (DMSO-d₆, δ): 1.35 (9H, s), 1.49-1.75 (6H, m), 1.93-2.1.2 (2H, m),3.11 (2H, t, J=9 Hz), 3.28-3.58 (7H, m), 3.92-4.02 (1H, m), 4.48 (2H, t,J=9 Hz), 4.67-4.79 (1H, m), 4.90-4.94 (1H, m), 6.55-7.02 (4H, m),7.32-7.60 (2H, m), 7.99-8.05 (1H, m), 8.61-8.63 (1H, m)

MS (ES+) m/z 565 (M+1)

Preparation 152

tert-Butyl[(3R)-1-(1-benzofuran-2-ylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (DMSO-d₆, δ): 1.34 (9H, s), 1.49-1.76 (6H, m), 1.87-2.19 (2H, m),2.52-2.99 (4H, m), 3.49-3.59 (1H, m), 3.65-3.78 (2H, m), 3.90-4.03 (1H,m), 4.67-4.80 (1H, m), 4.89-4.96 (1H, m), 6.56 (1H, d, J=16 Hz), 6.66(1H, s), 7.17-7.29 (2H, m), 7.34 (1H, d, J=8 Hz), 7.47-7.59 (3H, m),7.95-8.01 (1H, m), 8.55-8.59 (1H, m)

MS (ES+) m/z 563 (M+1)

Preparation 153

tert-Butyl[(3R)-1-(1-benzofuran-5-ylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl)-2-pyridyl)carbamate

NMR (DMSO-d₆, δ): 1.35 (9H, s), 1.49-1.76 (6H, m), 1.89-2.19 (2H, m),2.43-2.81 (4H, m), 3.41-3.66 (3H, m), 3.90-4.04 (1H, m), 4.67-4.80 (1H,m), 4.91-4.97 (1H, m), 6.60 (1H, d, J=16 Hz), 6.88 (1H, d, J=2 Hz), 7.10(1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.42 (1H, s), 7.46 (1H, d, J=8Hz), 7.55 (1H, d, J=16 Hz), 7.95 (1H, d, J=2 Hz), 8.01 (1H, d, J=8 Hz),8.62 (1H, s)

MS (ES+) m/z 563 (M+1)

Preparation 154

To a solution of tert-butyl4-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxylate(2.8 g) in EtOH (20 ml) was added 4N HCl in dioxane (18.6 ml), themixture was stirred at 23° C. for 30 minutes. The precipitate wascollected, washed with IPE, dried under reduced pressure to give ethyl(2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride.

NMR (DMSO-d₆, δ): 1.25(3H, t, J=7.0 Hz), 1.6-2.0(2H, m), 2.0-2.3 (2H,m), 2.8-3.1(2H, m), 3.33-3.40(2H, m), 4.18(2H, q, J=7.0 Hz), 6.58(1H, d,J=16.0 Hz), 7.11(1H, d, J=9.7 Hz), 7.65(1H, d, J=16.0 Hz), 8.24-8.28(2H,m), 9.11(2H, brs)

Mass (APCI): 276(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 154.

Preparation 155

Ethyl (2E)-3-[5-chloro-6-(4-piperidylamino)-3-pyridyl]acrylatedihydrochloride

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.8-2.8(4H, m), 2.8-3.1(2H, m),3.2-3.4(2H, m), 4.16(2H, q, J=7.4 Hz), 6.44(1H, d, J=16.0 Hz), 7.53(1H,d, J=16.0 Hz), 8.17(1H, d, J=2.0 Hz), 8.30(1H, d, J=2.0 Hz)

Mass (APCI): 310(M+H)+

Preparation 156

Ethyl (2E)-3-(6-[methyl(4-piperidyl)amino]-3-pyridyl}acrylatedihydrochloride

NMR (DMSO-d₆, δ): 1.25(3H, t, J=7.4 Hz), 1.80-1.86(2H, m), 2.10-2.26(2H,m), 2.95-3.20(2H, m), 3.04(3H, s), 3.27-3.39(2H, m), 4.18(2H, q, J=7.4Hz), 4.60-4.85(1H, m), 6.64(1H, d, J=16.0 Hz), 7.27(1H, d, J=8.0 Hz),7.67(1H, d, J=16.0 Hz), 8.31-8.36(2H, m), 9.10-6.40(2H, m)

Mass (APCI): 290(M+H)+

Preparation 157

To an ice-cooled solution of ethyl(2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg)and Et₃N (0.448 ml) in DMF (8 ml) was added benzoyl chloride (124 mg),the mixture was stirred at 23° C. for 1 hour. The mixed solution waspoured into water (20 ml). The precipitate was collected, washed withwater, dried under reduced pressure to give ethyl(2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylate.

NMR (DMSO-d₆, δ): 1.33(3H, t, J=7.0 Hz), 1.22-1.46(2H, m), 2.04-2.30(2H,m), 3.00-3.30(2H, m), 3.50-4.20(2H, m), 4.20(2H, q, J=7.0 Hz),4.50-4.80(2H, m), 6.22(1H, d, J=15.8 Hz), 6.39(1H, d, J=8.8 Hz),7.32-7.46(5H, m), 7.46-7.63(2H, m), 8.19(1H, d, J=2.1 Hz)

Mass (APCI): 380(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 157.

Preparation 158

Ethyl(2E)-3-(6-{[1-(4-fluorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.32(3H, t, J=7.1 Hz), 1.30-1.60(2H, m), 2.10-2.30(2H,m), 3.00-3.30(2H, m), 3.99-4.14(2H, m), 4.25(2H, q, J=7.1 Hz), 4.68(1H,d, J=7.8 Hz), 6.22(1H, d, J=16.0 Hz), 6.39(1H, d, J=8.8 Hz),7.07-7.13(2H, m), 7.39-7.64(4H, m), 8.19(1H, d, J=2.2 Hz)

Mass (APCI): 398(M+H)+

Preparation 159

Ethyl(2E)-3-(6-{[1-(4-methylbenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.32(3H, t, J=7.1 Hz), 1.30-1.60(2H, m), 2.10-2.30(2H,m), 2.37(3H, s), 3.00-3.30(2H, m), 3.99-4.14(2H, m), 4.25(2H, q, J=7.1Hz), 4.68(1H, d, J=7.8 Hz), 6.21(1H, d, J=16.0 Hz), 6.38(1H, d, J=8.8Hz), 7.18-7.34(4H, m), 8.18-7.56-7.63(2H, m), 8.18(1H, d, J=2.0 Hz)

Mass (APCI): 394(M+H)+

Preparation 160

Ethyl(2E)-3-(6-{[1-(4-methoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.32(3H, t, J=7.1 Hz), 1.30-1.60(2H, m), 2.10-2.30(2H,m), 3.00-3.30(2H, m), 3.80(3H, s), 3.99-4.14(2H, m), 4.25(2H, q, J=7.1Hz), 4.68(1H, d, J=7.8 Hz), 6.21(1H, d, J=16.0 Hz), 6.28(1H, d, J=8.8Hz), 7.92(2H, d, J=8.8 Hz), 7.39(2H, d, J=8.8 Hz), 7.53-7.64(2H, m),8.18(1H, d, J=2.0 Hz)

Mass (APCI): 410(M+H)+

Preparation 161

Ethyl(2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-5-chloro-3-pyridyl}acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.2 Hz), 1.5-2.1(4H, m), 2.70-3.25(2H,m), 3.50-3.70(1H, m), 4.15(2H, q, J=7.2 Hz), 4.20-4.60(2H, m), 6.48(1H,d, J=16.0 Hz), 6.74(1H, d, J=8.0 Hz), 7.3-7.55(6H, m), 8.12(1H, d, J=2.0Hz), 8.29(1H, d, J=2.0 Hz)

Mass (APCI): 436(M+Na)+

Preparation 162

Ethyl(2E)-3-(5-chloro-6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.2 Hz), 1.5-2.1(4H, m), 2.70-3.25(2H,m), 3.50-3.70(1H, m), 4.15(2H, q, J=7.2 Hz), 4.20-4.60(2H, m), 6.49(1H,d, J=16.0 Hz), 6.72(1H, d, J=8.0 Hz), 7.30-7.60(5H, m), 8.12(1H, d,J=2.0 Hz), 8.29(1H, d, J=2.0 Hz)

Mass (APCI): 470(M+Na)+

Preparation 163

Ethyl(2E)-3-(5-chloro-6-{[1-(3-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.53-1.94(4H, m), 2.75-3.30(2H,m), 3.45-3.70(1H, m), 4.60(2H, q, J=7.4 Hz), 4.20-4.60(2H, m), 6.49(1H,d, J=16.0 Hz), 6.72(1H, d, J=7.0 Hz), 7.33-7.56(5H, m), 8.13(1H, d,J=2.0 Hz), 8.30(1H, d, J=2.0 Hz)

Preparation 164

Ethyl(2E)-3-(5-chloro-6-{[1-(2-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

Mass (ESI): 448(M+H)+

Preparation 165

Ethyl(2E)-3-(6-[[1-(4-chlorobenzoyl)-4-piperidyl](methyl)amino]-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.55-1.99(4H, m), 2.80-3.87(3H,m), 3.08(3H, s), 4.15(2H, q, J=7.4 Hz), 4.50-5.00(2H, m), 6.40(1H, d,J=16.0 Hz), 6.73(1H, d, J=8.8 Hz), 7.45-7.58(4H, m), 7.93(1H, dd, J=2.0,8.8 Hz), 8.34(1H, d, J=2.0 Hz)

Mass (APCI): 428(M+H)+

Preparation 166

To a suspension of(2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (170 mg)in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (62.3mg), EDCI HCl (102 mg), HOBt (71.9 mg), Et₃N (0.201 ml), the mixture wasstirred at 23° C. for 8 hours. The mixed solution was poured into amixture of water (20 ml) and AcOEt (20 ml). The organic layer wasseparated, washed with water twice and brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography eluted with 8% MeOH in dichloromethane to give(2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(50 mg).

NMR (DMSO-d₆, δ): 1.20-1.70(8H, m), 1.80-2.10(4H, m), 3.00-3.30(2H, m),3.40-3.80(2H, m), 3.80-4.20(2H, m), 4.20-4.50(1H, m), 4.87(1H, s),6.19(1H, d, J=16.0 Hz), 6.52(1H, d, J=8.8 Hz), 7.07(1H, d, J=7.4 Hz),7.30-7.47(6H, m), 7.60(1H, d, J=8.8 Hz), 8.13(1H, d, J=2.0 Hz),11.03(1H, brs).

Mass (APCI): 451(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 166.

Preparation 167

(2E)-3-(6-{[1-(4-Fluorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.20-1.80(6H, m), 1.80-2.10(2H, m), 3.01-3.25(2H, m),3.50-3.60(2H, m), 4.90-4.18(2H, m), 4.33(1H, brs), 4.87(1H, s), 6.20(1H,m), 6.52(1H, d, J=8.8 Hz), 6.96(1H, d, J=4.0 Hz), 7.26-7.36(2H, m),7.44-7.48(2H, m), 7.60(1H, d), 8.14(1H, s), 11.04(1H, s)

Mass (APCI): 491(M+Na)+

Preparation 168

(2E)-3-(6-{[1-(4-Methylbenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.24-1.80(6H, m), 1.80-2.10(2H, m), 2.33(3H, s),3.10-3.29(2H, m), 3.43-3.70(2H, m), 3.90-4.15(2H, m), 4.33(1H, brs),4.87(1H, s), 6.20(1H, d, J=15.4 Hz), 6.52(1H, d, J=8.8 Hz), 7.07(1H, d,J=7.3 Hz), 7.23-7.29(3H, m), 7.34(1H, d, J=15.4 Hz), 7.60(1H, d, J=8.8Hz), 8.14(1H, s)

Mass (APCI): 465(M+H)+

Preparation 169

(2E)-3-(6-{[1-(4-Methoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.20-1.45(4H, m), 1.50-1.60(3H, m), 1.30-1.75(3H, m),1.80-2.0(2H, m), 2.90-3.20(2H, m), 3.50-3.55(1H, m), 3.95-4.20(2H, m),4.87(1H, s), 6.20(1H, d, J=15.4 Hz), 6.53(1H, d, J=8.8 Hz), 6.98(2H, d,J=8.8 Hz), 7.07(1H, d, J=7.4 Hz), 7.33-7.37(3H, m), 7.60(1H, d, J=8.8Hz), 8.1(1H, s), 11.04(1H, s)

Mass (APCI): 503(M+Na)+

Preparation 170

(2E)-3-[6-({1-[4-(1H-Pyrrol-1-yl)benzoyl]-4-piperidyl}amino)-3-pyridyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.30-1.80(9H, m), 1.85-2.10(2H, m), 3.10-3.20(2H, m),3.45-3.60(1H, m), 3.80-4.20(2H, m), 4.88(1H, s), 6.25-6.35(2H, m),6.53(1H, d, J=8.8 Hz), 7.10(1H, d, J=7.3 Hz), 7.35(1H, d, J=16.0 Hz),7.43-7.84(7H, m), 8.15(1H, d, J=2.0 Hz), 11.04(1H, s)

Preparation 171

N-(4-Chlorophenyl)-4-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-1-piperidinecarboxamide

NMR (DMSO-d₆, δ): 1.20-1.80(8H, m), 1.80-2.10(2H, m), 2.85-3.13(2H, m),3.40-3.46(1H, m), 3.84-4.12(4H, m), 4.88(1H, s), 6.23(1H, d, J=16.0 Hz),6.53(1H, d, J=8.8 Hz), 7.13-7.70(7H, m), 8.15(1H, d, J=2.0 Hz), 8.66(1H,s), 11.04(1H, brs)

Mass (APCI): 522(M+Na)+

Preparation 172

N-(4-Methylphenyl)-4-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-1-piperidinecarboxamide

NMR (DMSO-d₆, δ): 1.20-1.45(3H, m), 1.50-1.60(3H, m), 1.30-1.75(3H, m),1.80-2.0(2H, m), 2.22(3H, s), 2.90-3.20(2H, m), 3.50-3.55(1H, m),3.95-4.07(4H, m), 4.89(1H, s), 6.20(1H, d, J=15.4 Hz), 6.51(1H, d, J=8.8Hz), 7.02(2H, d, J=8.8 Hz), 7.07(1H, d, J=7.4 Hz), 7.33(2H, d, J=8.8Hz), 7.36(1H, d, J=15.4 Hz), 7.60(1H, d, J=8.8 Hz), 8.15(1H, s),8.42(1H, s), 11.05(1H, s)

Mass (APCI): 502(M+Na)+

Preparation 173

N-(4-Methoxyphenyl)-4-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-1-piperidinecarboxamide

NMR (DMSO-d₆, δ): 1.20-1.45(3H, m), 1.50-1.60(3H, m), 1.30-1.75(3H, m),1.80-2.0(2H, m), 2.90-3.20(2H, m), 3.50-3.55(2H, m), 3.70(3H, s),3.95-4.07(4H, m), 4.87(1H, s), 6.20(1H, d, J=15.4 Hz), 6.51(1H, d, J=8.8Hz), 6.81(2H, d, J=8.8 Hz), 7.07(1H, d, J=7.4 Hz), 7.32-7.37(3H, m),7.60(1H, d, J=8.8 Hz), 8.15(1H, s), 8.37(1H, s), 11.05(1H, s)

Mass (APCI): 518(M+Na)+

Preparation 174

(2E)-3-(6-[(1-Benzoyl-4-piperidyl)amino]-5-chloro-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.56-2.00(11H, m), 2.60-3.30(2H, m), 3.40-3.70(2H, m),3.89-4.10(1H, m), 4.20-4.60(2H, m), 4.88(1H, s), 6.33(1H, d, J=15.7 Hz),6.64(1H, d, J=8.0 Hz), 7.33-7.48(6H, m), 7.86(1H, s), 8.21(1H, s),11.08(1H, s)

Mass (APCI): 507(M+Na)+

Preparation 175

(2E)-3-(5-Chloro-6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.56-2.00(11H, m), 2.60-3.30(2H, m), 3.40-3.70(2H, m),3.89-4.10(1H, m), 4.20-4.60(2H, m), 4.88(1H, s), 6.31(1H, d, J=15.7 Hz),6.62(1H, d, J=8.0 Hz), 7.33-7.55(5H, m), 7.86(1H, s), 8.21(1H, s),11.08(1H, s)

Mass (APCI): 541(M+Na)+

Preparation 176

To a suspension of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylatedihydrochloride (500 mg) in DMF (5 ml) was added4-(1H-pyrrol-1-yl)benzoic acid (309 mg), EDCI HCl (317 mg), HOBt (223mg), Et₃N (0.63 ml), the mixture was stirred at 23° C. for 8 hours. Themixed solution was poured into a mixture of water (20 ml) and AcOEt (20ml). The organic layer was separated, washed with water twice and brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluted with 5% MeOH indichloromethane to give ethyl(2E)-3-[6-({1-[4-(1H-pyrrol-1-yl)benzoyl]-4-piperidyl}amino)-3-pyridyl]acrylate(686 mg).

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.40-1.55(2H, m), 1.80-2.10(2H,m), 3.10-3.30(2H, m), 3.55-3.80(1H, m), 4.14(2H, q, J=7.4 Hz),4.20-4.40(1H, m), 6.28-6.36(3H, m), 6.52(1H, d, J=8.8 Hz), 7.20(1H, d,J=7.4 Hz), 7.44-7.51(5H, m), 7.66(2H, d, J=8.6 Hz), 7.46-7.83(1H, m),8.23(1H, d, J=2.0 Hz)

Mass (APCI): 445(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 176.

Preparation 177

Ethyl(2E)-3-(5-chloro-6-{[1-(4-phenoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.45-3.00(4H, m), 4.15(2H, q,J=7.4 Hz), 4.25-4.60(2H, m), 6.49(1H, d, J=16.0 Hz), 6.75(1H, d, J=8.4Hz), 7.01-7.24(5H, m), 7.39-7.47(4H, m), 7.41(1H, d, J=16.0 Hz), 7.12(1H, d, J=2.0 Hz), 8.29(1H, d, J=2.0 Hz)

Mass (APCI): 528(M+Na)+

Preparation 178

To an ice-cooled solution of ethyl(2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg)and Et₃N (0.448 ml) in DMF (3 ml) was added 1-chloro-4-isocyanatobenzene(136 mg), the mixture was stirred at 23° C. for 1 hour. The mixedsolution was poured into water (20 ml). The precipitate was collected,washed with hexane and water, dried under reduced pressure to give ethyl(2E)-3-{6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate(341 mg).

NMR (DMSO-d₆, δ): 1.20-1.63(7H, m), 2.10-2.19(2H, m), 3.04-3.19(3H, m),3.94-4.03(3H, m), 4.23(2H, q, J=7.0 Hz), 4.67(1H, d, J=7.8 Hz), 6.20(1H,d, J=16.0 Hz), 6.36-6.45(2H, m), 7.21-7.34(5H, m), 7.53-7.64(2H, m),8.20(1H, d, J=2.0 Hz)

Mass (APCI): 429(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 178.

Preparation 179

Ethyl(2E)-3-{6-[(1-{[(4-methylphenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate

NMR (DMSO-d₆, δ): 1.32(3H, t, J=7.1 Hz), 1.40-1.60(2H, m), 2.10-2.18(2H,m), 2.29(3H, s), 3.90-4.14(2H, m), 4.25(2H, q, J=7.1 Hz), 7.42(1H, d,J=7.8 Hz), 6.22(1H, d, J=16.0 Hz), 6.36-6.40(2H, m), 7.08(2H, d, J=8.8Hz), 7.22(2H, d, J=8.8 Hz), 7.54(1H, d, J=16.0 Hz), 7.62(1H, dd, J=2.0,8.8 Hz), 8.19(1H, d, J=2.0 Hz)

Mass (APCI): 431(M+Na)+

Preparation 180

Ethyl(2E)-3-{6-[(1-{[(4-methoxyphenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate

Mass (APCI): 425(M+H)+

Preparation 181

Ethyl(2E)-3-{5-chloro-6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.50-1.67(2H, m), 1.82-1.88(2H,m), 2.84-2.96(2H, m), 4.10-4.26(3H, m), 4.15(2H, q, J=7.4 Hz), 6.49(1H,d, J=16.0 Hz), 6.78(1H, d, J=8.0 Hz), 7.26(2H, d, J=8.8 Hz), 7.49(2H, d,J=8.8 Hz), 7.50(1H, d, J=16.0 Hz), 8.12(1H, d, J=2.0 Hz), 8.30(1H, d,J=2.0 Hz), 8.68(1H, s)

Preparation 182

To a solution of ethyl(2E)-3-{5-chloro-6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate(363 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOH aq (2.35 ml),the mixture was stirred at 80° C. for 1 hour. The pH of the mixture wasadjusted to ca.4.5 with 1N HCl aq. The solution was evaporated underreduced pressure to give crude3-{5-Chloro-6-[1-(4-chlorophenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylicacid.

To a suspension of crude3-{5-Chloro-6-[1-(4-chlorophenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylicacid (247 mg) in DMF (3 ml) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (73.1 mg), EDCI (96.9 mg),HOBt (84.3 mg,), the mixture was stirred at 23° C. for 8 hours. Themixed solution was poured into a mixture of water (20 ml) and AcOEt (20ml). The organic layer was separated, washed with water twice and brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluted with 5% MeOH indichloromethane to give4-[(3-chloro-5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-(4-chlorophenyl)-1-piperidinecarboxamide(246 mg).

NMR (DMSO-d₆, δ): 1.45-1.95(10H, m), 2.75-3.00(2H, m), 3.45-3.50(1H, m),3.80-4.30(3H, m), 4.89(1H, s), 6.31(1H, d, J=16.0 Hz), 6.68(1H, d, J=8.4Hz), 7.27(2H, d, J=8.8 Hz), 7.36(1H, d, J=16.0 Hz), 7.51(2H, d, J=8.8Hz), 7.85(1H, s), 8.22(1H, s), 8.68(1H, s)

Mass (APCI): 556(M+Na)+

The following compounds were obtained according to a similar manner tothat of Preparation 182.

Preparation 183

(2E)-3-(5-Chloro-6-{[1-(3-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

Mass (ESI): 519(M+H)+

Preparation 184

(2E)-3-(5-Chloro-6-{[1-(2-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

Mass (ESI): 519(M+H)+

Preparation 185

(2E)-3-{6-[(1-Benzyl-4-piperidyl]amino}-5-chloro-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.40-2.35(11H, m), 2.80-3.10(2H, m), 3.40-3.75(3H, m),3.82-4.15(2H, m), 4.88(1H, s), 6.32(1H, d, J=16.0 Hz), 9.59(1H, m),7.20-7.40(6H, m), 7.84(1H, s), 8.20(1H, s), 11.10(1H, s)

Preparation 186

(2E)-3-(5-Chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.45-1.85(9H, m), 1.90-2.10(2H, m), 2.28(3H, s),2.75-2.85(2H, m), 3.41(2H, s), 3.49-3.55(1H, m), 3.85-4.10(2H, m),4.89(1H, s), 6.31(1H, d, J=16.0 Hz), 6.50(1H, d, J=7.0 Hz), 7.11(2H, d,J=8.8 Hz), 7.18(2H, d, J=8.8 Hz), 7.36(1H, d, J=16.0 Hz), 7.83(1H, s),8.20(1H, s), 11.08(1H, brs)

Preparation 187

(2E)-3-(5-Chloro-6-{[1-(4-methoxybenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.45-1.90(11H, m), 1.90-2.15(2H, m), 2.78-2.84(2H, m),3.40(2H, s), 3.48-3.55(1H, m), 3.74(3H, s), 3.80-4.05(2H, m), 4.89(1H,s), 6.30(1H, d, J=16.0 Hz), 6.50(1H, d, J=7.0 Hz), 6.88(1H, d, J=8.8Hz), 7.20(1H, d, J=8.8 Hz), 7.35(1H, d, J=16.0 Hz), 7.83(1H, s),8.20(1H, s), 11.08(1H, s)

Preparation 188

(2E)-3-(5-Chloro-6-[(1-isobutyl-4-piperidyl)amino]-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 0.86(6H, d, J=6.5 Hz), 1.40-2.10(15H, m),2.70-2.90(2H, m), 3.45-3.70(1H, m), 3.80-4.00(2H, m), 4.88(1H, brs),6.30(1H, d, J=16.0 Hz), 6.50(1H, d, J=8.0 Hz), 7.35(1H, d, J=16.0 Hz),7.83(1H, s), 8.20(1H, s), 11.06(1H, brs)

Preparation 189

(2E)-3-(5-Chloro-6-{[1-(cyclopropylmethyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 0.05-0.15(2H, m), 0.42-0.51(2H, m), 0.75-0.95(1H, m),1.40-2.30(14H, m), 2.90-3.15(2H, m), 3.40-3.60(1H, m), 3.80-4.10(2H, m),4.89(1H, s), 6.31(1H, d, J=16.0 Hz), 6.53(1H, d, J=8.0 Hz), 7.35(1H, d,J=16.0 Hz), 7.85(1H, s), 8.21(1H, s), 11.07(1H, brs)

Preparation 190

(2E)-3-{6-[[1-(4-Chlorobenzoyl)-4-piperidyl](methyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.40-1.90(11H, m), 2.75-3.30(2H, m), 2.90(3H, s),3.45-3.60(2H, m), 3.85-4.10(1H, m), 4.45-4.90(3H, m), 6.27(1H, d, J=16.0Hz), 6.74(1H, d, J=8.8 Hz), 7.39(1H, d, J=16.0 Hz), 7.45-7.55(4H, m),7.74(1H, dd, J=2.0, 8.8 Hz), 8.27(1H, d, J=2.0 Hz), 11.08(1H, brs)

Preparation 191

(2E)-3-(5-Chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.50-19.0(7H, m), 2.08-2.29(1H, m), 2.37-2.65(2H, m),2.78-2.87(1H, m), 3.40-3.65(1H, m), 3.57(2H, s), 3.86-4.12(1H, m),4.45-4.55(1H, m), 4.89(1H, s, J=16.0 Hz), 6.32(1H, d, J=7.0 Hz),6.62(1H, d), 7.09-7.17(2H, m), 7.85-7.30-7.40(3H, m), 8.20-7.85(1H, s),8.20(1H, s), 11.08(1H, brs)

Preparation 192

(2E)-3-(5-Chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.45-1.90(7H, m), 2.10-2.30(1H, m), 2.27(3H, s),2.36-2.84(3H, m), 3.45-3.53(1H, m), 3.60(2H, s), 3.94-4.05(1H, m),4.40-4.60(1H, m), 4.89(1H, s), 6.32(1H, d, J=16.0 Hz), 6.60(1H, d, J=7.0Hz), 7.10(2H, d, J=8.8 Hz), 7.28(2H, d, J=8.8 Hz), 7.36(1H, d, J=16.0Hz), 7.84(1H, s), 8.20(1H, s), 11.08(1H, brs)

Preparation 193

(2E)-3-(5-Chloro-6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.76-1.92(7H, m), 2.12-2.30(1H, m), 2.32-2.86(3H, m),3.40-3.60(1H, m), 3.51(2H, s), 3.72(3H, s), 3.86-4.05(1H, m),4.35-4.60(1H, m), 4.89(1H, s), 6.31(1H, d, J=16.0 Hz), 6.61(1H, d, J=7.0Hz), 6.86(2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz), 7.35(1H, d, J=16.0Hz), 7.84(1H, s), 8.19(1H, s), 11.07(1H, brs)

Preparation 194

To a solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylatedihydrochloride (309 mg) in EtOH (5 ml) was added Et₃N (0.921 ml), thenbenzaldehyde (0.117 ml) and titanium(IV) isopropoxide (0.463 ml), themixture was stirred at 23° C. for 12 hours. To the mixture was addedsodium borohydride, the mixture was stirred at 23° C. for 24 hours. Thereaction mixture was poured into sat.NaHCO₃aq. (20 ml)-AcOEt (20 ml),the insoluble material was removed by filtration, then the filtrate wasextracted with ethyl acetate. The extracts were washed with water, driedover magnesium sulfate and concentrated. The residue was purified bysilica gel column chromatography eluted with 5% MeOH in dichloromethaneto give ethyl(2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}acrylate (328mg).

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.55-1.68(4H, m), 1.95-2.07(2H,m), 2.75-2.87(2H, m), 3.46(2H, s), 3.90-4.10(1H, m), 4.15(2H, q, J=7.4Hz), 6.47(1H, d, J=16.0 Hz), 6.63(1H, d, J=8.0 Hz), 7.21-7.37(5H, m),7.50(1H, d, J=16.0 Hz), 8.10(1H, d, J=2.0 Hz), 8.27(1H, d, J=2.0 Hz).

Mass (APCI): 400(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 194.

Preparation 195

Ethyl(2E)-3-(5-chloro-6-{[1-(4-chlorobenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.2 Hz), 1.50-2.10(6H, m), 2.67-2.89(2H,m), 3.46(2H, s), 3.89-4.10(1H, m), 4.15(2H, q, J=7.2 Hz), 6.47(1H, d,J=16.0 Hz), 6.63(1H, d, J=8.0 Hz), 7.30-7.41(4H, m), 7.50(1H, d, J=16.0Hz), 8.10(1H, d, J=2.0 Hz), 8.27(1H, d, J=2.0 Hz)

Mass (APCI): 434(M+H)+

Preparation 196

Ethyl(2E)-3-(5-chloro-6-{[1-(4-fluorobenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.55-1.68(4H, m), 1.95-2.07(2H,m), 2.75-2.87(2H, m), 3.46(2H, s), 3.90-4.10(1H, m), 4.15(2H, q, J=7.4Hz), 6.47(1H, d, J=16.0 Hz), 6.63(1H, d, J=8.0 Hz), 7.09-7.38(4H, m),7.50(1H, d, J=16.0 Hz), 8.10(1H, d, J=2.0 Hz), 8.27(1H, d, J=2.0 Hz).

Mass (APCI): 418(M+H)+

Preparation 197

tert-Butyl 4-(methylamino)-1-piperidinecarboxylate

NMR (DMSO-d₆, δ): 0.95-1.12(2H, m), 1.38(9H, s), 1.68-1.76(2H, m),2.25(3H, s), 2.30-2.40(1H, m), 2.65-2.95(2H, m), 3.32(1H, brs),3.70-3.85(2H, m).

Preparation 198

To a solution of ethyl(2E)-3-[5-chloro-6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride(710 mg) in CH₂Cl₂ (14 ml) was added Et₃N (0.517 ml), the mixture wasstirred at 23° C. for 30 minutes. To the mixture was added4-Methyl-benzaldehyde (0.241 ml) and SODIUM triacetoxyborohydride (590mg), the mixture was stirred at 23° C. for 24 hours. The reactionmixture was poured into sat.NaHCO₃aq. (20 ml)-AcOEt (20 ml). The organiclayer was washed with water, dried over magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography eluted with 5% MeOH in dichloromethane to give ethyl(2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate(671 mg).

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.50-1.87(4H, m), 1.94-2.05(2H,m), 2.28(3H, s), 2.77-2.83(2H, m), 3.41(2H, s), 3.85-4.07(1H, m),4.15(2H, q, J=7.4 Hz), 6.47(1H, d, J=16.0 Hz), 6.62(1H, d, J=7.0 Hz),7.11(2H, d, J=8.8 Hz), 7.18(2H, d, J=8.8 Hz), 7.50(1H, d, J=16.0 Hz),8.10(1H, d, J=2.0 Hz), 8.27(1H, d, J=2.0 Hz),

The following compounds were obtained according to a similar manner tothat of Preparation 198.

Preparation 199

Ethyl(2E)-3-(5-chloro-6-{[1-(4-methoxybenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.21(3H, t, J=7.4 Hz), 1.56-1.89(4H, m), 1.90-2.15(2H,m), 2.78-2.84(2H, m), 3.40(2H, s), 3.74(3H, s), 3.85-4.10(1H, m),4.16(2H, q, J=7.4 Hz), 6.47(1H, d, J=16.0 Hz), 6.61(2H, d, J=8.8 Hz),7.20(2H, d, J=8.8 Hz), 7.50(1H, d, J=16.0 Hz), 8.09(1H, d, J=2.0 Hz),8.27(1H, d, J=2.0 Hz)

Preparation 200

Ethyl(2E)-3-{5-chloro-6-[(1-isobutyl-4-piperidyl)amino]-3-pyridyl}acrylate

Mass (ESI): 366(M+H)+

Preparation 201

Ethyl(2E)-3-(5-chloro-6-{[1-(cyclopropylmethyl)-4-piperidyl]amino}-3-pyridyl)acrylate

Mass (ESI): 364(M+H)+

Preparation 202

To a solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (5.0g) in DMF (50 ml) was added 4-fuluorobenzylchloride (3.38 ml) andN,N-diisopropylethylamine (9.35 ml), the mixture was stirred at 70° C.for 2 hours. The mixed solution was poured into a mixture of water (300ml) and AcOEt (30 0 ml). The organic layer was separated, washed withwater twice and brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatographyeluted with 5% MeOH in dichloromethane to give[1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester(6.8 g). To a solution of [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (6.8 g) in MeOH (34 ml) was treated with 4N HCl inAcOEt (29 ml) and was stirred at 25° C. for 12 hours.

The solvent was removed under reduced pressure. Recrystallization(acetonitrile-MeOH) provided (3R)-1-(4-fluorobenzyl)-3-pyrrolidinaminedihydrochloride as white solid (3.77 g).

NMR (DMSO-d₆, δ): 1.96-2.55(2H, m), 3.10-3.78(4H, m), 3.80-4.22(1H, m),4.47-4.52(2H, m), 7.26-7.36(2H, m), 7.61-7.72(2H, m), 8.60-8.90(2H, m),11.50-11.99(1H, m)

Mass (APCI): 195(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 202.

Preparation 203

(3R)-1-(4-Methylbenzyl)-3-pyrrolidinamine dihydrochloride

NMR (DMSO-d₆, δ): 1.96-2.55(2H, m), 2.33(3H, s), 3.10-3.78(4H, m),3.80-4.22(1H, m), 4.47-4.52(2H, m), 7.25(2H, d, J=8.8 Hz), 7.50(2H,brs), 8.73-8.23(2H, m), 11.39-11.87(1H, m).

Mass (APCI): 191(M+H)+

Preparation 204

(3R)-1-(4-Methoxybenzyl)-3-pyrrolidinamine dihydrochloride

NMR (DMSO-d₆, δ): 1.90-2.30(2H, m), 3.10-3.75(4H, m), 3.78(3H, s),3.80-4.15(1H, m), 7.37(2H, brs), 7.00(2H, d, J=8.8 Hz), 7.54(2H, brs),8.67-8.76(2H, m)

Mass (APCI): 206(M+H)+

Preparation 205

To a solution of (3R)-1-(4-fluorobenzyl)-3-pyrrolidinaminedihydrochloride (3.5 g) in DMF (35 ml) was added 5,6-dichloronicotinicacid ethyl ester (3.38 ml) and K₂CO₃ (6.34 g), the mixture was stirredat 100° C. for 4 hours under N₂ atmosphere. The mixed solution waspoured into a mixture of water (250 ml) and AcOEt (250 ml). The organiclayer was separated, washed with water twice and brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluted with AcOEt:hexane=1:2 to giveethyl5-chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}nicotinate(3.75 g).

NMR (DMSO-d₆, δ): 1.28(3H, t, J=7.4 Hz), 1.73-1.98(1H, m), 2.10-2.30(1H,m), 2.40-2.70(3H, m), 2.82-2.87(1H, m), 3.57(2H, s), 4.25(2H, q, J=7.4Hz), 4.51-4.61(1H, m), 4.02-7.18(3H, m), 7.31-7.38(2H, m), 7.93(1H, d,J=2.0 Hz), 8.54(1H, d, J=2.0 Hz)

Mass (APCI): 378(M+H)+

The following compounds were obtained according to a similar manner tothat of Preparation 205.

Preparation 206

Ethyl5-chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}nicotinate

NMR (DMSO-d₆, δ): 1.24(3H, t, J=7.4 Hz), 1.76-1.95(1H, m), 2.12-2.34(1H,m), 2.27(3H, s), 2.45-2.70(3H, m), 2.71-2.85(1H, m), 3.54(2H, s),4.24(2H, q, J=7.4 Hz), 4.46-4.60(1H, m), 7.00-7.21(5H, m), 7.93(1H, d,J=2.0 Hz), 8.53(1H, d, J=2.0 Hz)

Mass (APCI): 374(M+H)+

Preparation 207

Ethyl5-chloro-6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}nicotinate

Mass (ESI): 390(M+H)+

Preparation 208

To a solution of 2-chloro-5-iodopyridine (37.7 g) in DMF (300 mL) wasadded palladium(II) acetate (1.77 g), tri-o-tolylphosphine (7.19 g),diisopropylethylamine (82 mL), and ethyl acrylate (17.9 mL), and themixture was heated at 100° C. for 10 hours. Resulting mixture was pouredinto water and extracted with AcOEt. The organic layer was washed withwater and brine and dried over Na₂SO₄, and the solvent was removed invacuo. Obtained brown solid was suspended in a mixture of hexane andAcOEt (4:1), and the precipitate was filtered off. The filtrate wasconcentrated in vacuo, and residual brown oil was purified by silica gelcolumn chromatography eluted with AcOEt and hexane (1:4-1:2). Resultingsolid was triturated with IPE to give ethyl(2E)-3-(6-chloro-3-pyridyl)acrylate as pale yellow powder (20.58 g).

NMR (DMSO-d₆, δ): 1.35 (3H, t, J=7.0 Hz), 4.28 (2H, q, J=7.0 Hz), 6.49(1H, d, J=16.1 Hz), 7.37 (1H, d, J=8.1 Hz), 7.63 (1H, d, J=16.1 Hz),7.80 (1H, dd, J=8.2, 2.6 Hz), 8.52 (1H, d, J=2.6 Hz)

MS (ES+) m/z 212 (M+1)

Preparation 209

To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (14.3 g) indioxane (140 mL) was added palladium(II) acetate (1.52 g),2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (3.99 g), cesiumcarbonate (30.2 g), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (13.1 g),and the mixture was heated at 95° C. for 2.5 days. The resulting mixturewas poured into sat.NH₄Cl aqueous solution and extracted with AcOEt. Theorganic layer was washed with sat. NH₄Cl aq solution, water, and brine,and dried over Na₂SO₄. The solvent was removed in vacuo and residualbrown oil was purified by silica gel column chromatography eluted withAcOEt to give ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate aspale yellow oil (10.7 g)

NMR (DMSO-d₆, δ): 1.32 (3H, t, J=7.0 Hz), 1.70 (1H, m), 2.39 (2H, m),2.61 (1H, m), 2.75 (1H, m), 2.84 (1H, m), 3.64 (2H, d, J=2.2 Hz), 4.24(2H, q, J=7.0 Hz), 4.35 (1H, m), 5.09 (1H, d, J=8.0 Hz), 6.20 (1H, d,J=16.1 Hz), 6.36 (1H, d, J=8.8 Hz), 7.27 (2H, m), 7.32 (3H, m), 7.56(1H, d, J=15.8 Hz), 7.60 (1H, d, J=8.8, 2.2 Hz), 8.19 (1H, d, J=2.2 Hz)

MS (ES+) m/z 352 (M+1)

Preparation 210

To a solution of ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (11g) in THF (105 mL) was added di-tert-butyl bicarbonate (13.7 g) and4-dimethylaminopyridine (95.6 mg), and the mixture was heated at 60° C.for 13 hours. The solvent was removed in vacuo and residual oil waspurified by silica gel column chromatography eluted with AcOEt to giveethyl(2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylateas pale yellow oil (13.0 g).

NMR (DMSO-d₆, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.08 (1H, m),2.23 (1H, m), 2.57-2.73 (3H, m), 2.93 (1H, t, J=8.8 Hz), 3.53 (1H, d,J=12.6 Hz), 3.63 (1H, d, J=12.8 Hz), 4.29 (2H, q, J=7.0 Hz), 4.91 (1H,m), 6.46 (1H, d, J=16.1 Hz), 7.20-7.27 (5H, m), 7.29 (1H, d, J=8.8 Hz),7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.2 Hz), 8.53 (1H, d,J=2.2 Hz)

MS (ES+) m/z 452 (M+1)

Preparation 211

To a solution of ethyl(2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylateas pale yellow oil (16.6 g) in toluene (80 mL) was addeddiisopropylethylamine (2.17 mL) and 1-chloroethyl chloridecarbonate(5.76 mL) at 5° C. The mixture was warmed to ambient temperature andstirred for 1 hour, and diluted with IPE (150 mL). The precipitate wasremoved by filtration and the solvent was removed in vacuo. Residualcolorless oil was purified by silica gel column chromatography elutedwith AcOEt and hexane (1:2-1:1). Obtained oil was dissolved in EtOH (70mL) and heated at 70° C. for 1 hour. The solvent was removed in vacuo togive ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylatedihydrochloride (8.9 g) as pale yellow oil.

NMR (DMSO-d₆, δ): 1.27 (3H, t, J=7.0 Hz), 1.42 (9H, s), 1.98 (1H, m),2.23 (1H, m), 3.15 (1H, m), 3.34 (3H, br), 4.21 (2H, q, J=7.0 Hz), 4.96(1H, m), 6.78 (1H, d, J=16.1 Hz), 7.45 (1H, d, J=8.4 Hz), 7.70 (1H, d,J=16.1 Hz), 8.25 (1H, dd, J=8.6, 2.2 Hz), 8.75 (1H, d, J=2.2 Hz),

MS (ES+) m/z 362 (M+1)

Preparation 212

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylatedihydrochloride (3.0 g) in 1,2-dichloroethane (30 mL) was addeddiisopropylethylamine (2.41 mL) and 3-fluorobenzaldehyde (857 mg), andthe mixture was stirred at room temperature for 5 minutes. To themixture was added sodium triacetoxyborohydride (3.1 g) and stirred for 3hours, and resulting mixture was poured into sat NH₄Cl aq solution, andextracted with AcOEt. The organic layer was washed with sat NH₄Cl aqsolution, water, and brine, and dried over Na₂SO₄. The solvent wasremoved in vacuo and the residual oil was purified by silica gel columnchromatography eluted with AcOEt and hexane (1:1) to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(2.40 g) as colorless oil.

NMR (DMSO-d₆, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.09 (1H, m),2.24 (1H, m), 2.64 (2H, t, J=7.4 Hz), 2.74 (1H, dd, J=9.2, 7.0 Hz), 2.89(1H, t, J=8.1 Hz), 3.51 (1H, d, J=13.3 Hz), 3.62 (1H, d, J=13.3 Hz),4.28 (2H, q, J=7.0 Hz), 4.91 (1H, m), 6.47 (1H, d, J=16.1 Hz), 6.91 (2H,m), 6.99 (1H, d, J=8.0 Hz), 7.21 (1H, m), 7.28 (1H, d, J=8.4 Hz), 7.66(1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.2 Hz)

MS (ES+) m/z 470 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 212.

Preparation 213

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.31 (9H, s), 1.36 (3H, t, J=7.0 Hz), 1.44 (9H, s),1.97-2.32 (2H, m), 2.53-2.77 (3H, m), 2.89-3.01 (1H, m), 3.54 (1H, d,J=12.1 Hz), 3.60 (1H, d, J=12.1 Hz), 4.83-4.98 (1H, m), 6.47 (1H, d,J=16.1 Hz), 7.16 (2H, d, J=8.1 Hz), 7.23-7.34 (1H, m), 7.30 (2H, d,J=8.1 Hz), 7.67 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54(1H, d, J=2.6 Hz)

MS (ES+) m/z 508.36

Preparation 214

Ethyl(2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[4-(trifluoromethyl)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate

NMR (DMSO-d₆, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 1.97-2.14 (1H,m), 2.16-2.31 (1H, m), 2.56-2.79 (3H, m), 2.88-2.97 (1H, m), 3.59 (1H,d, J=13.2 Hz), 3.67 (1H, d, J=13.2 Hz), 4.29 (2H, q, J=7.0 Hz),4.83-4.99 (1H, m), 6.47 (1H, d, J=16.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.35(2H, d, J=8.1 Hz), 7.53 (2H, d, J=8.1 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80(1H, dd, J=8.4, 2.6 Hz), 8.53 (1H, d, J=2.6 Hz)

MS (ES+) m/z 520.32(M+1)

Preparation 215

Ethyl(2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[4-(trifluoromethoxy)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate

NMR (DMSO-d₆, δ): 1.35 (3H, t, J=7.3 Hz), 1.43 (9H, s), 1.97-2.32 (2H,m), 2.53-2.77 (3H, m), 2.87-2.98 (1H, m), 3.54 (1H, d, J=13.2 Hz), 3.62(1H, d, J=13.2 Hz), 4.29 (2H, q, J=7.3 Hz), 4.83-4.97 (1H, m), 6.47 (1H,d, J=16.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.25 (2H, d, J=8.1 Hz), 7.29 (1H,d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz),8.53 (1H, d, J=2.6 Hz)

MS (ES+) m/z 536.24(M+1)

Preparation 216

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 0.69-0.95 (2H, m), 1.02-1.48 (3H, m), 1.35 (3H, t, J=7.0Hz), 1.45 (9H, s), 1.52-1.80 (6H, m), 1.92-2.34 (4H, m), 2.41-2.74 (3H,m), 2.80-3.02 (1H, m), 4.29 (2H, q, J=7.0 Hz), 4.82-4.98 (1H, m), 6.46(1H, d, J=16.1 Hz), 7.31 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz),7.81 (1H, dd, J=8.4, 2.6 Hz), 8.86 (1H, d, J=2.6 Hz)

MS (ES+) m/z 458.37(M+1)

Preparation 217

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(1-cyclohexen-1-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d₆, δ): 1.35 (3H, q, J=7.0 Hz), 1.45 (9H, s), 1.48-1.73 (4H,m), 1.83-2.09 (5H, m), 2.14-2.32 (1H, m), 2.45-2.67 (3H, m), 2.77-2.99(3H, m), 4.28 (2H, q, J=7.0 Hz), 4.80-4.95 (1H, m), 5.52 (1H, brs), 6.46(1H, d, J=16.1 Hz), 7.31 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz),7.81 (1H, dd, J=8.4, 2.6 Hz), 8.56 (1H, d, J=2.6 Hz)

MS (ES+) m/z 456.54(M+1)

Preparation 218

Ethyl(2E)-3-{6-[[(3R)-1-(1-benzofuran-2-ylmethyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7 Hz), 1.43 (9H, s), 2.01-2.35 (2H, m),2.70-3.23 (4H, m), 3.76-3.90 (2H, m), 4.28 (2H, q, J=7 Hz), 4.90-5.02(1H, m), 6.42 (1H, d, J=16 Hz), 6.57 (1H, s), 7.17-7.27 (2H; m), 7.29(1H, d, J=8 Hz), 7.42-7.54 (2H, m), 7.61 (1H, d, J=16 Hz), 7.76 (1H, dd,J=2, 8 Hz), 8.45 (1H, d, J=2 Hz)

MS (ES+) m/z 492 (M+1)

Preparation 219

Ethyl(2E)-3-(6-{[(3R)-1-(1-benzofuran-5-ylmethyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7 Hz), 1.43 (9H, s), 2.06-2.42 (2H, m),2.79-3.27 (4H, m), 3.80-3.96 (2H, m), 4.29 (2H, q, J=7 Hz), 4.91-5.04(1H, m), 6.45 (1H, d, J=16 Hz), 6.73-6.75 (1H, m), 7.28 (2H, d, J=8 Hz),7.44 (1H, d, J=8 Hz), 7.57-7.67 (3H, m), 7.78 (1H, dd, J=2, 8 Hz), 8.49(1H, d, J=2 Hz)

MS (ES+) m/z 492 (M+1)

Preparation 220

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.07 (1H, m), 2.24(1H, m), 2.58-2.76 (3H, m), 2.94 (1H, m), 3.53 (1H, d, J=12.8 Hz), 3.61(1H, d, J=12.8 Hz), 4.29 (2H, q, J=7.0 Hz), 4.91 (1H, m), 6.47 (1H, d,J=16.1 Hz), 6.76-6.83 (3H, m), 7.19 (1H, t, J=8.1 Hz), 7.29 (1H, d,J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz), 8.54(1H, d, J=2.2 Hz)

MS (ES+) m/z 482 (M+1)

Preparation 221

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-phenylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 1.45 (9H, s), 1.78 (2H, m), 2.01(1H, m), 2.19 (1H, m), 2.36-2.77 (7H, m), 3.02 (1H, t, J=8.4 Hz), 4.28(2H, q, J=7.0 Hz), 4.89 (1H, m), 6.44 (1H, d, J=16.1 Hz), 7.14-7.19 (3H,m), 7.23-7.28 (2H, m), 7.31 (1H, d, J=8.4 Hz), 7.65 (1H, d, J=16.1 Hz),7.80 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.6 Hz)

MS (ES+) m/z 480 (M+1)

Preparation 222

Ethyl(2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[4-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate

NMR (CDCl₃, δ): 1.36 (3H, t, J=7.1 Hz), 1.45 (9H, s), 2.19 (1H, br),2.46 (1H, br), 2.96 (6H, s), 3.14 (2H, br), 3.42 (1H, br), 3.92 (1H,br), 4.29 (2H, q, J=7.1 Hz), 5.04 (1H, br), 6.45 (1H, d, J=16.1 Hz),6.69 (2H, d, J=8.8 Hz), 7.29 (3H, m), 7.63 (1H, d, J=16.1 Hz), 7.79 (1H,dd, J=8.4, 2.5 Hz), 8.46 (1H, br)

MS (ES+) m/z 495 (M+1)

Preparation 223

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.20 (1H, m), 2.52(1H, m), 3.29 (3H, m), 3.60 (1H, m), 3.86 (3H, s), 4.18 (2H, br), 4.28(2H, q, J=7.0 Hz), 5.10 (1H, m), 6.44 (1H, d, J=16.1 Hz), 6.91 (1H, d,J=7.4 Hz), 6.98 (1H, dd, J=7.5, 1.1 Hz), 7.32 (1H, d, J=84 Hz), 7.35(1H, td, J=7.8, 1.8 Hz), 7.50 (1H, dd, J=7.7, 1.1 Hz), 7.63 (1H, d,J=16.1 Hz), 7.79 (1H, dd, J=8.4, 2.2 Hz), 8.44 (1H, d, J=2.2 Hz)

MS (ES+) m/z 482 (M+1)

Preparation 224

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.11 (1H, br),2.33 (1H, br), 2.89 (3H, br), 3.13 (1H, br), 3.82 (1H, br), 4.29 (2H, q,J=7.0 Hz), 4.97 (1H, br), 6.45 (1H, d, J=16.1 Hz), 7.02 (1H, t, J=8.0Hz), 7.11 (1H, t, J=7.3 Hz), 7.25 (1H, br), 7.31 (1H, d, J=8.8 Hz), 7.40(1H, br), 7.65 (1H, d, J=16.1 Hz), 7.79 (1H, dd, J=8.4, 2.6 Hz), 8.49(1H, d)

MS (ES+) m/z 470 (M+1)

Preparation 225

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (DMSO-d, 6): 1.36 (3H, t, J=7.0 Hz), 1.45 (9H, s), 2.20 (1H, m),2.43 (1H, m), 3.17 (3H, br), 3.44 (1H, br), 4.29 (2+2H, q, J=7.0 Hz),5.09 (1H, m), 6.45 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.55 (1H,tm, J=7.0 Hz), 7.63 (1H, d, J=16.1 Hz), 7.70 (1H, dd, J=7.0, 1.5 Hz),7.73 (1H, dd, J=7.0, 1.7 Hz), 7.79 (1H, dd, J=8.8, 2.2 Hz), 7.82 (1H, d,J=8.4 Hz), 7.06 (1H, d, J=8.4 Hz), 7.26 (1H, d, J=8.4 Hz), 8.50 (1H, d,J=2.2 Hz)

MS (ES+) m/z 503 (M+1)

Preparation 226

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-isoquinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.0 Hz), 1.45 (9H, s), 2.12 (1H, m), 2.25(1H, m), 2.72 (2H, m), 2.81 (1H, m), 2.89 (1H, m), 3.72 (1H, m), 3.75(1H, d, J=12.8 Hz), 3.84 (1H, d, J=12.8 Hz), 4.30 (2H, q, J=7.0 Hz),4.93 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.28 (1H, d, J=8.0 Hz), 7.54 (1H,m), 7.65 (1H, d, J=16.1 Hz), 7.70 (1H, m), 7.79 (2H, m⁻¹), 8.00 (1H,br), 8.10 (1H, d, J=8.4 Hz), 8.51 (1H, d, J=2.2 Hz), 8.83 (1H, d, J=2.2Hz)

MS (ES+) m/z 503 (M+1)

Preparation 227

Ethyl(2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[(5-methyl-2-thienyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 1.45 (9H, s), 2.06 (1H, br),2.22 (1H, br), 2.44 (3H, s), 2.64 (1H, br), 2.74 (2H, br), 3.01 (1H,br), 3.72 (2H, br), 4.27 (2H, q, J=7.0 Hz), 4.91 (1H, m) 6.46 (1H, d,J=16.1 Hz), 6.54 (1H, br), 6.64 (1H, br), 7.31 (1H, d, J=8.4 Hz), 7.66(1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.2 Hz)

MS (ES+) m/z 472 (M+1)

Preparation 228

Ethyl(2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[(5-methyl-2-furyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate

NMR (CDCl₃, δ): 1.36 (3H, t, J=7.0 Hz), 1.46 (9H, s), 2.14 (1H, m), 2.29(3H, s), 2.39 (1H, m), 3.10 (3H, br), 3.42 (1H, br), 3.89 (2H, br), 4.29(2H, q, J=7.0 Hz), 5.03 (1H, m), 5.95 (1H, br), 6.28 (1H, br), 6.46 (1H,d, J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.65 (1H, d, J=16.1 Hz), 7.81(1H, dd, J=8.4, 2.2 Hz), 8.50 (1H, d)

MS (ES+) m/z 456 (M+1)

Preparation 229

Ethyl(2E)-3-{6-[(tert-butoxycarbonyl)((3R)-1-{(2E)-3-[4-(dimethylamino)phenyl]-2-propen-1-yl}-3-pyrrolidinyl)amino]-3-pyridyl}acrylate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 1.47 (9H, s), 2.33 (2H, br),2.61 (2H, br), 2.99 (6H, s), 3.45 (2H, br), 3.82 (2H, br), 4.28 (2H, q,J=7.0 Hz), 5.12 (1H, m), 6.19 (1H, dt, J=15.4, 7.0 Hz), 6.44 (1H, d,J=16.1 Hz), 6.63 (1H, d, J=15.4 Hz), 6.66 (2H, d, J=9.2 Hz), 7.31 (2H,d, J=8.8 Hz), 7.31 (1H, d, J=8.8 Hz), 7.63 (1H, d, J=16.1 Hz), 7.80 (1H,dd, J=8.4, 2.6 Hz), 8.47 (1H, br)

MS (ES+) m/z 521 (M+1)

Preparation 230

Ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,2-dimethylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 0.81 (9H, s), 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.01(1H, m), 2.17 (2H, br.), 2.66 (2H, br.), 2.88 (2H, br.), 4.28 (2H, q,J=7.0 Hz), 4.86 (1H, br.), 6.46 (1H, d, J=16.1 Hz), 7.31 (1H, d, J=8.4Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.1, 2.2 Hz), 8.56 (1H, d,J=2.2 Hz)

MS (ES+) m/z 432 (M+1)

Preparation 231

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(2.40 g) in MeOH (10 mL) and dioxane (10 mL) was added 1N NaOH aqsolution (10.2 mL), and the mixture was stirred for 3 hours at ambienttemperature. The pH value of the mixture was adjusted to 7 with 1N HCl,and the solvent was removed in vacuo. Obtained solid was suspended intoluene and the residual water was geotropically removed to give(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid and the crude product was used in next reaction without furtherpurification.

NMR (DMSO-d₆, δ): 1.36 (9H, s), 1.99 (1H, m), 2.12 (1H, m), 2.62 (1H,dd, J=8.9, 7.0 Hz), 2.74 (1H, t, J=8.2 Hz), 3.46 (1H, d, J=13.6 Hz),3.58 (1H, d, J=13.6 Hz), 4.76 (1H, m), 6.66 (1H, d, J=16.1 Hz), 6.95(1H, m), 7.03 (1H, m), 7.29 (1H, m), 1.32 (1H, m), 7.33 (1H, d, J=8.4Hz), 7.62 (1H, d, J=16.1 Hz), 8.16 (1H, dd, J=8.4, 2.6 Hz), 8.69 (1H, d,J=2.2 Hz)

MS (ES+) m/z 442 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 231.

Preparation 232

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.36 (9H, s), 1.96 (1H, m), 2.12 (1H, m), 2.62 (1H,m), 2.77 (1H, m), 3.45 (1H, d, J=17.5 Hz), 3.53 (1H, d, J=17.5 Hz), 3.71(3H, s), 4.75 (1H, m), 6.66 (1H, d, J=16.1 Hz), 6.76 (3H, m), 7.16 (1H,t, J=8.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.63 (1H, d, J=15.8 Hz), 8.16 (1H,dd, J=8.4, 2.2 Hz), 8.69 (1H, d, J=2.2 Hz)

MS (ES+) m/z 454 (M+1)

Preparation 233

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-(3-phenylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.37 (9H, s), 1.62 (2H, m), 1.93 (1H, m), 2.06 (1H,m), 2.27 (1H, m), 2.29 (2H, m), 2.55 (1H, m), 2.79 (2H, m), 4.73 (1H,m), 6.61 (1H, d, J=16.1 Hz), 7.15 (3H, m), 7.24 (2H, m), 7.32 (1H, d,J=8.4 Hz), 7.52 (1H, d, J=16.1 Hz), 8.12 (1H, d, J=8.4, 2.2 Hz), 8.66(1H, d, J=2.2 Hz)

MS (ES+) m/z 452 (M+1)

Preparation 234

(2E)-3-[6-((tert-Butoxycarbonyl){(3R)-1-[4-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylicacid

NMR (DMSO-d₆, δ): 1.37 (9H, s), 2.03 (1H, m), 2.24 (1H, m), 2.89 (6H,s), 4.00 (2H, br), 4.90 (1H, m), 6.66 (1H, d, J=16.1 Hz), 6.69 (2H, d,J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.38 (1H, d, J=8.1 Hz), 7.63 (1H, d,J=16.1 Hz), 8.19 (1H, dd, J=8.1, 2.2 Hz), 8.66 (1H, d, J=2.2 Hz)

MS (ES+) m/z 467 (M+1)

Preparation 235

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.34 (9H, s), 1.93 (1H, m), 2.09 (1H, m), 2.61 (1H,m), 2.72 (1H, m), 3.43 (1H, d, J=14.3 Hz), 3.52 (1H, d, J=14.3 Hz), 3.72(3H, s), 4.69 (1H, m), 6.48 (1H, d, J=16.1 Hz), 6.82 (1H, t, J=8.1 Hz),6.91 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=8.1 Hz), 7.09 (1H, d, J=16.1 Hz),7.19 (2H, m), 7.93 (1H, dd, J=8.4, 2.2 Hz), 8.49 (1H, d, J=2.2 Hz)

MS (ES+) m/z 454 (M+1)

Preparation 236

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.35 (9H, s), 1.96 (1H, br), 2.10 (1H, br), 2.61 (1H,br), 2.81 (1H, br), 3.46 (1H, m), 3.58 (1H, m), 4.73 (1H, br), 6.66 (1H,d, J=16.1 Hz), 7.13 (2H, m), 7.25 (2H, m), 7.33 (1H, d, J=8.4 Hz), 7.62(1H, d, J=16.1 Hz), 8.15 (1H, dd, J=8.4, 2.2 Hz), 8.67 (1H, d, J=2.2 Hz)

MS (ES+) m/z 442 (M+1)

Preparation 237

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.40 (9H, s), 2.09 (1H, m), 2.35 (1H, m), 3.16 (2H,br), 4.50 (2H, br), 5.04 (1H, br), 6.67 (1H, d, J=16.1 Hz), 7.44 (1H, d,J=8.4 Hz), 7.64 (1H, d, J=16.1 Hz), 7.64 (2H, m), 7.79 (1H, t, J=7.7Hz), 8.00 (3H, m), 8.21 (1H, dd, J=8.4, 2.2 Hz), 8.43 (1H, d, J=8.1 Hz),8.71 (1H, s)

MS (ES+) m/z 475 (M+1)

Preparation 238

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(3-isoquinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.35 (9H, s), 2.00 (1H, m), 2.14 (1H, m), 2.58 (2H,m), 2.67 (1H, m), 2.84 (1H, m), 3.68 (1H, d, J=13.9 Hz), 3.78 (1H, d,J=13.9 Hz), 4.77 (1H, m), 6.65 (1H, d, J=16.1 Hz), 7.33 (1H, d, J=8.4Hz), 7.58 (1H, t, J=7.7 Hz), 7.61 (1H, d, J=16.1 Hz), 7.72 (1H, t, J=8.1Hz), 7.93 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.4 Hz), 8.10 (1H, s), 8.15(1H, dd, J=8.4, 2.2 Hz), 8.66 (1H, d, J=2.2 Hz), 8.74 (1H, d, J=2.2 Hz)

MS (ES+) m/z 475 (M+1)

Preparation 239

(2E)-3-[6-((tert-Butoxycarbonyl){(3R)-1-[(5-methyl-2-thienyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylicacid

NMR (DMSO-d₆, δ): 1.36 (9H, s), 1.94 (1H, m), 2.08 (1H, m), 2.37 (3H,s), 2.58 (1H, m), 2.82 (1H, m), 3.57 (1H, d, J=13.5 Hz), 3.65 (1H, d,J=13.5 Hz), 4.72 (1H, m), 6.58 (1H, m), 6.65 (1H, d, J=2.9 Hz), 6.66(1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=16.1 Hz),8.15 (1H, d, J=8.4, 2.2 Hz), 8.68 (1H, d, J=2.2 Hz)

MS (ES+) m/z 444 (M+1)

Preparation 240

(2E)-3-[6-((tert-Butoxycarbonyl){(3R)-1-[(5-methyl-2-furyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylicacid

NMR (DMSO-d₆, δ): 1.37 (9H, s), 1.97 (4H, m), 2.15 (4H, m), 2.23 (3H,s), 2.90 (2H, br), 3.85 (2H, br), 4.82 (1H, m), 6.04 (1H, br), 6.28 (1H,br), 6.67 (1H, d, J=16.1 Hz), 7.37 (1H, d, J=8.4 Hz), 7.62 (1H, d,J=16.1 Hz), 8.18 (1H, dd, J=8.4, 2.2 Hz), 8.67 (1H, d, J=2.2 Hz),

MS (ES+) m/z 428 (M+1)

Preparation 241

(2E)-3-{6-[(tert-Butoxycarbonyl)((3R)-1-{(2E)-3-[4-(dimethylamino)phenyl]-2-propen-1-yl}-3-pyrrolidinyl)amino]-3-pyridyl}acrylicacid

NMR (DMSO-d₆, δ): 1.40 (9H, s), 2.07 (1H, m), 2.28 (1H, m), 2.92 (6H,s), 3.17 (2H, d), 3.81 (2H, br), 5.00 (1H, br), 6.04 (1H, m), 6.65 (1H,d, J=16.1 Hz), 6.69 (1H, d, J=8.1 Hz), 6.69 (2H, d, J=8.1 Hz), 7.30 (2H,d, J=8.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=16.1 Hz), 8.20 (1H,br.d, J=8.4 Hz), 8.68 (1H, br)

MS (ES+) m/z 493 (M+1)

Preparation 242

(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2,2-dimethylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 0.75 (9H, s), 1.37 (9H, s), 1.94 (1H, m), 2.05 (1H,m), 2.07 (1H, d, J=13.1 Hz), 2.15 (1H, d, J=13.1 Hz), 2.58 (2H, m), 2.77(2H, m), 4.73 (1H, m), 6.64 (1H, d, J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz),7.60 (1H, d, J=16.1 Hz), 8.15 (1H, dd, J=8.4, 2.2 Hz), 8.70 (1H, d,J=2.2 Hz)

MS (ES+) m/z 404 (M+1)

Preparation 243

To a solution of(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid (2.25 g, crude) in DMF (23 mL) was added was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (776 mg), HOBt (1.03 g), andEDCI (1.19 g) and the resulting mixture was stirred at ambienttemperature for 3 hours. The reaction mixture was diluted with water andextracted with AcOEt. The organic phase was washed with sat NH₄Cl aqsolution, sat NaHCO₃ aq solution, and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue was purified by silica gelcolumn chromatography eluted with AcOEt to give tert-butyl[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate(2.51 mg) as pale yellow form.

NMR (CDCl₃, δ): 1.44 (9H, s), 1.63 (3H, br), 1.87 (3H, br), 2.08 (1H,m), 2.23 (1H, m), 2.63 (2H, t, J=7.3 Hz), 2.73 (1H, dd, J=9.2, 7.3 Hz),2.88 (1H, t, J=8.0 Hz), 3.51 (1H, d, J=13.2 Hz), 3.62 (1H, d, J=13.2Hz), 3.67 (1H, m), 3.99 (1H, m), 4.90 (1H, m), 5.05 (1H, br), 6.41 (1H,br), 6.91 (2H, m), 6.98 (1H, m), 7.21 (1H, m), 7.27 (1H, m), 7.70 (1H,d, J=16.1 Hz), 7.78 (1H, dd, J=8.8, 2.2 Hz), 8.56 (1H, d, J=2.2 Hz)

MS (ES+) m/z 541 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 243.

Preparation 244

tert-Butyl[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.44 (9H, s), 1.64 (3H, br), 1.87 (3H, br), 2.08 (1H,m), 2.25 (1H, m), 2.70 (3H, br), 2.97 (1H, br), 3.63 (2H, m), 3.70 (1H,m), 3.98 (1H, m), 4.91 (1H, m), 5.03 (1H, br), 6.40 (1H, br), 6.78 (1H,br.d, J=8.4 Hz), 6.83 (2H, br.d, J=7.0 Hz), 7.19 (1H, t, J=7.7 Hz), 7.28(1H, d, J=7.7 Hz), 7.69 (1H, d, J=16.1 Hz), 7.77 (1H, dd, J=8.4 and 2.2Hz), 8.55 (1H, d, J=2.0 Hz)

MS (ES+) m/z 553 (M+1)

Preparation 245

tert-Butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)[(3R)-1-(3-phenylpropyl)-3-pyrrolidinyl]carbamate

NMR (CDCl₃, δ): 1.45 (9H, s), 1.63 (3H, br), 1.82 (2H, br), 1.86 (3H,br), 2.03 (1H, br), 2.23 (1H, br), 2.51 (2H, br), 2.60 (1H, m), 2.73(2H, br), 3.05 (1H, br), 3.69 (1H, m), 3.97 (1H, m), 4.91 (1H, m), 5.02(1H, br), 6.31 (1H, br), 7.17 (3H, m), 7.27 (2H, m), 7.29 (1H, d, J=8.4Hz), 7.68 (1H, d, J=16.1 Hz), 7.77 (1H, dd, J=8.4 and 2.2 Hz), 8.55 (1H,br)

MS (ES+) m/z 551 (M+1)

Preparation 246

tert-Butyl{(3R)-1-[4-(dimethylamino)benzyl]-3-pyrrolidinyl}(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.44 (9H, s), 1.63 (3H, br), 1.87 (3H, br), 2.08 (1H,br), 2.28 (1H, br), 2.78 (3H, br), 2.93 (3H, s), 3.07 (1H, br), 3.63(2H, br), 3.68 (1H, m), 3.99 (1H, m), 4.94 (1H, br), 5.04 (1H, br), 6.44(1H, br), 6.67 (1H, d, J=8.1 Hz), 7.16 (2H, br.d, J=7.0 Hz), 7.28 (1H,d, J=8.4 Hz), 7.68 (1H, d, J=16.1 Hz), 7.75 (1H, d, J=8.4 Hz), 8.52 (1H,s)

MS (ES+) m/z 566 (M+1)

Preparation 247

tert-Butyl[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.44 (9H, s), 1.63 (3H, br), 1.86 (3H, br), 2.05 (1H,br), 2.26 (1H, br), 2.68 (1H, br), 2.77 (2H, br), 3.03 (1H, br), 3.68(2H, br), 3.80 (2H, s), 3.97 (1H, m), 4.92 (1H, m), 5.03 (1H, br), 6.43(1H, br), 6.84 (1H, d, J=8.1 Hz), 6.88 (1H, t, J=7.4 Hz), 7.22 (2H, m),7.29 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=16.1 Hz), 7.75 (1H, d, J=8.1 Hz),8.53 (1H, s)

MS (ES+) m/z 553 (M+1)

Preparation 248

tert-Butyl[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.43 (9H, s), 1.63 (3H, br), 1.86 (3H, br), 2.05 (1H,m), 2.23 (1H, m), 2.72 (3H, m), 2.99 (1H, m), 3.64 (1H, d, J=12.8 Hz),3.69 (1H, d, J=12.8 Hz), 3.71 (1H, m), 4.91 (1H, m), 5.04 (1H, s), 6.43(1H, br), 7.00 (1H, t, J=8.4 Hz), 7.07 (1H, d, J=7.7 Hz), 7.24 (2H, m),7.28 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=16.1 Hz), 7.75 (1H, dd, J=8.4,2.2 Hz), 8.52 (1H, d, J=2.2 Hz)

MS (ES+) m/z 541 (M+1)

Preparation 249

tert-Butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]carbamate

NMR (CDCl₃, δ): 1.45 (9H, s), 1.63 (3H, br), 1.87 (3H, br), 2.12 (1H,br), 2.29 (1H, br), 2.74 (1H, br), 2.80 (1H, br), 3.04 (1H, br), 3.68(1H, m), 3.94 (2H, d), 3.98 (1H, m), 4.96 (1H, br), 5.03 (1H, br), 6.36(1H, br), 7.29 (1H, d, J=8.4 Hz), 7.46 (1H, m), 7.53 (1H, d, J=8.1 Hz),7.69 (2H, m), 7.78 (2H, m), 8.07 (2H, m), 8.55 (1H, br)

MS (ES+) m/z 574 (M+1)

Preparation 250

tert-Butyl[(3R)-1-(3-isoquinolinylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.43 (9H, s), 1.64 (3H, br), 1.86 (3H, br), 2.09 (1H,m), 2.25 (1H, m), 2.70 (2H, m), 2.82 (1H, m), 2.94 (1H, m), 3.67 (1H,m), 3.73 (1H, d, J=13.6 Hz), 3.82 (1H, d, J=13.6 Hz), 3.99 (1H, m), 4.92(1H, m), 5.05 (1H, br), 6.48 (1H, br), 7.25 (1H, d, J=7.5 Hz), 7.54 (1H,t, J=7.5 Hz), 7.69 (2H, m), 7.76 (2H, m), 8.00 (1H, br), 8.10 (1H, d,J=8.8 Hz), 8.51 (1H, br), 8.80 (1H, dd, J=1.8 Hz)

MS (ES+) m/z 574 (M+1)

Preparation 251

tert-Butyl{(3R)-1-[(5-methyl-2-thienyl)methyl]-3-pyrrolidinyl}(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.44 (9H, s), 1.64 (3H, br), 1.87 (3H, br), 2.05 (1H,m), 2.22 (1H, m), 2.64 (1H, m), 2.74 (2H, m), 3.01 (1H, t), 3.66 (1H,m), 3.69 (1H, d, J=13.6 Hz), 3.75 (1H, d, J=13.2 Hz), 3.98 (1H, m), 4.90(1H, m), 5.03 (1H, br), 6.43 (1H, br), 6.54 (1H, d, J=2.9 Hz), 6.64 (1H,d, J=3.3 Hz), 7.30 (1H, d, J=8.4 Hz), 7.69 (1H, d, J=16.1 Hz), 7.77 (1H,d, J=8.4, 2.6 Hz), 8.55 (1H, br),

MS (ES+) m/z 543 (M+1)

Preparation 252

tert-Butyl{(3R)-1-[(5-methyl-2-furyl)methyl]-3-pyrrolidinyl}(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.45 (9H, s), 1.63 (3H, br), 1.86 (3H, br), 2.03 (1H,m), 2.22 (1H, m), 2.26 (3H, s), 2.59 (1H, q, J=8.4 Hz), 2.69 (1H, t,J=8.6 Hz), 2.82 (1H, m), 3.11 (1H, t, J=8.4 Hz), 3.55 (1H, d, J=13.9Hz), 3.62 (1H, d, J=13.6 Hz), 3.66 (1H, m), 3.98 (1H, m), 4.92 (1H, m),5.03 (1H, br), 5.86 (1H, dd, J=2.9, 1.0 Hz), 6.03 (1H, d, J=2.9 Hz),6.40 (1H, br), 7.30 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=15.4 Hz), 7.76(1H, dd, J=8.4 and 2.2 Hz), 8.53 (1H, d, J=2.2 Hz)

MS (ES+) m/z 527 (M+1)

Preparation 253

tert-Butyl((3R)-1-{(2E)-3-[4-(dimethylamino)phenyl]-2-propen-1-yl}-3-pyrrolidinyl)(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 1.45 (9H, s), 1.62 (3H, br), 1.85 (3H, br), 2.05 (1H,br), 2.26 (1H, br), 2.69 (1H, br), 2.86 (2H, br), 3.18 (1H, br), 3.28(2H, br), 3.66 (1H, m), 3.98 (1H, m), 4.93 (1H, m), 5.02 (1H, br), 6.06(1H, dt, J=15.8 and 6.6 Hz), 6.43 (1H, d, J=15.4 Hz), 6.54 (1H, br),6.67 (2H, d, J=8.8 Hz), 7.25 (2H, d, J=8.1 Hz), 7.29 (1H, d, J=8.4 Hz)”7.67 (1H, d, J=16.1 Hz), 7.76 (1H, d, J=8.4 Hz), 8.53 (1H, s)

MS (ES+) m/z 592 (M+1)

Preparation 254

tert-Butyl[(3R)-1-(2,2-dimethylpropyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate

NMR (CDCl₃, δ): 0.81 (9H, s), 1.44 (9H, s), 1.62 (3H, br), 1.86 (3H,br), 2.01 (1H, m), 2.17 (3H, m), 2.67 (2H, m), 2.88 (2H, m), 3.67 (1H,m), 3.97 (1H, m), 4.86 (1H, m), 5.03 (1H, br), 6.41 (1H, br), 7.30 (1H,d, J=8.4 Hz), 7.71 (1H, br.d, J=15.8 Hz), 7.78 (1H, d, J=8.1 Hz), 8.58(1H, s),

MS (ES+) m/z 503 (M+1)

Preparation 255

To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate (300 mg) intoluene (3 mL) was added palladium(II) acetate (26.4 mg),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg), cesiumcarbonate (583 mg), and (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (291mg). The mixture was heated at 90° C. for 2 days. The resulting mixturewas poured into sat.NH₄Cl aq solution and extracted with AcOEt. Theorganic layer was washed with sat. NH₄Cl aq solution, water, and brine,and dried over Na₂SO₄. The solvent was removed in vacuo and residualbrown oil was purified by preparative thin layer chromatography(chloroform:methanol 95:5) to give ethyl(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate(297 mg) as pale yellow form.

NMR (CDCl₃, δ): 1.33 (3H, t, J=7.1 Hz), 2.00 (1H, m), 2.23 (0.5H, m),2.36 (0.5H, m), 3.35 (0.5H, m), 3.60 (1.5H, m), 3.81 (1H, m), 4.03 (1H,m), 4.10 (1H, m), 4.24 (2H, q, J=7.1 Hz), 6.22 (0.5H, d, J=15.8 Hz),6.24 (0.5H, d, J=15.8 Hz), 6.51 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=8.1Hz), 7.33-7.62 (7H, m)

MS (ES+) m/z 399 (M+1)

Preparation 256

To a solution of ethyl(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate(297 mg) in dioxane (3 mL) was added 1N NaOH aq solution (2.23 mL), andthe mixture was heated at 70° C. for 18 hours. Resulting mixture wasdiluted with water and washed with ether. The pH value of aqueous phasewas adjusted to 5, and the precipitate was collected by filtration anddried in vacuo to give(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylicacid (103 mg) as pale yellow powder.

NMR (DMSO-d₆, δ): 1.88 (1H, m), 2.19 (1H, m), 3.25 (1H, m), 3.43 (1H,m), 3.59 (1H, m), 3.79 (1H, m), 4.07 (1H, m), 6.14 (0.5H, d, J=16.1 Hz),6.18 (0.5H, d, J=16.1 Hz), 6.57 (1H, d, J=8.8 Hz), 6.64 (1H, d, J=8.8Hz), 7.36-7.47 (2H, m), 7.50 (1H, s), 7.53 (2H, d, J=8.1 Hz), 7.57 (2H,d, J=8.1 Hz), 7.93 (1H, d, J=8.4 Hz)

MS (ES+) m/z 371 (M+1)

Preparation 257

To a solution of(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylicacid (103 mg) in DMF (2 mL) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (35.8 mg), HOBt (48.8 mg), andEDCI (56.1 mg) and the resulting mixture was stirred at ambienttemperature for 3 hours. The reaction mixture was diluted with water andextracted with AcOEt. The organic phase was washed with sat NH₄Cl aqsolution, sat NaHCO₃ aq solution, and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue was purified by preparativethin layer chromatography (chloroform:methanol 10:1) to give(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(76 mg) as pale yellow form.

NMR (DMSO-d₆, δ): 1.54 (3H, br), 1.68 (3H, br), 1.89 (1H, br), 2.19 (1H,br), 3.24 (1H, br), 3.53 (3H, br), 3.79 (1H, m), 3.95 (1H, br), 4.07(1H, br), 4.87 (1H, br), 6.17 (1H, br), 6.44 (0.5H, d, J=16.1 Hz), 6.46(0.5H, d, J=16.1 Hz), 6.57 (1H, d, J=8.8 Hz), 6.65 (1H, d, J=8.4 Hz),7.26-7.37 (3H, m), 7.47-7.58 (4H, m)

MS (ES+) m/z 470 (M+1)

Preparation 258

To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (3.5 g) indioxane (70 mL) was added palladium(II) acetate (371 mg) and2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (110 mg) andcesium carbonate (583 mg), and(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (4.09 g). The mixture washeated at 90° C. for 3 hours. The resulting mixture was diluted withAcOEt, and the precipitate was removed by filtration. The filtrate wasconcentrated and residual brown oil was purified by purified by silicagel column chromatography eluted with AcOEt and hexane (1:4)-AcOEt togive ethyl(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(2.16 g) as dark yellow form.

NMR (CDCl₃, δ): 1.33 (3H, t, J=7.0 Hz), 2.01 (1H, m), 2.35 (1H, m), 3.37(0.5H, dd, J=11.0, 5.5 Hz), 3.60 (1.5H, m), 3.78 (0.5H, m), 3.88 (1H,m), 4.04 (0.5H, m), 4.25 (2H, q, J=7.0 Hz), 4.53 (1H, m), 4.77 (0.5H, d,J=6.9 Hz), 4.89 (0.5H, d, J=6.6 Hz), 6.22 (0.5H, d, J=16.1 Hz), 6.26(0.5H, d, J=16.1 Hz), 6.38 (0.5H, d, J=8.4 Hz), 6.46 (0.5H, d, J=8.8Hz), 7.38 (2H, m), 7.48 (2H, m), 7.62 (2H, m), 8.16 (0.5H, s), 8.23(0.5H, s)

MS (ES+) m/z 400 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 258.

Preparation 259

Ethyl(2E)-3-(6-{[(3S)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate

NMR (CDCl₃, δ): 1.33 (3H, t, J=7.0 Hz), 2.01 (1H, m), 2.35 (1H, m), 3.37(0.5H, dd, J=11.0, 5.5 Hz), 3.60 (1.5H, m), 3.78 (0.5H, m), 3.88 (1H,m), 4.04 (0.5H, m), 4.25 (2H, q, J=7.0 Hz), 4.53 (1H, m), 4.77 (0.5H, d,J=6.9 Hz), 4.89 (0.5H, d, J=6.6 Hz), 6.22 (0.5H, d, J=16.1 Hz), 6.26(0.5H, d, J=16.1 Hz), 6.38 (0.5H, d, J=8.4 Hz), 6.46 (0.5H, d, J=8.8Hz), 7.38 (2H, m), 7.48 (2H, m), 7.62 (2H, m), 8.16 (0.5H, s), 8.23(0.5H, s)

MS (ES+) m/z 400 (M+1)

Preparation 260

To a solution of ethyl(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate(2.16 g) in MeOH (30 mL) and dioxane (30 mL) was added 1N NaOH aqsolution (27.1 mL). The mixture was heated at 70° C. for 1.5 hour anddiluted with water (120 mL) and washed with ether. The pH value ofaqueous phase was adjusted to 5.5, and the precipitate was collected byfiltration and dried in vacuo to give(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid (1.58 g) as pale yellow powder.

NMR (DMSO-d₆, δ): 1.93 (1H, m), 2.20 (1H, m), 3.25-3.72 (4H, m), 3.80(1H, m), 4.37 (0.5H, m), 4.50 (0.5H, m), 6.24 (0.5H, d, J=16.1 Hz), 6.27(0.5H, d, J=15.8 Hz), 6.52 (0.5H, d, J=8.9 Hz), 6.57 (0.5H, d, J=9.1Hz), 7.39-7.60 (5H, m), 7.77 (0.5H, dd, J=9.1, 2.2 Hz), 7.82 (0.5H, dd,J=9.1, 2.2 Hz), 8.15 (0.5H, d, J=2.2 Hz), 8.25 (0.5H, d, J=1.8 Hz)

MS (ES+) m/z 372 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 260.

Preparation 261

(2E)-3-(6-{[(3S)-1-(4-Chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid

NMR (DMSO-d₆, δ): 1.93 (1H, m), 2.20 (1H, m), 3.25-3.72 (4H, m), 3.80(1H, m), 4.37 (0.5H, m), 4.50 (0.5H, m), 6.24 (0.5H, d, J=16.1 Hz), 6.27(0.5H, d, J=15.8 Hz), 6.52 (0.5H, d, J=8.9 Hz), 6.57 (0.5H, d, J=9.1Hz), 7.39-7.60 (5H, m), 7.77 (0.5H, dd, J=9.1, 2.2 Hz), 7.82 (0.5H, dd,J=9.1, 2.2 Hz), 8.15 (0.5H, d, J=2.2 Hz), 8.25 (0.5H, d, J=1.8 Hz)

MS (ES+) m/z 372 (M+1)

Preparation 262

To a solution of(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylicacid (1.58 g) in DMF (16 mL) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (546 mg), HOBt (744 mg), andEDCI HCl (1.06 mg) and the resulting mixture was stirred at ambienttemperature for 4 hours. The reaction mixture was diluted with water andextracted with AcOEt. The organic phase was washed with sat NH₄Cl aqsolution and sat NaHCO₃ aq solution, and brine, and dried over Na₂SO₄.The solvent was removed in vacuo and the residue was purified by silicagel column chromatography eluted with chloroform:methanol=97.5:2.5 togive(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(1.89 g) as colorless oil.

NMR (DMSO-d₆, δ): 1.53 (brH, ), 1.69 (brH, ), 1.92 (mH, ), 2.19 (mH, ),3.23-3.70 (mH, ), 3.80 (mH, ), 3.95 (mH, ), 4.36 (mH, ), 4.49 (mH, ),4.87 (brH, ), 6.22 (dH, 16.1), 6.25 (dH, 16.1), 6.52 (dH, 8.8), 6.56(dH, 9.1), 7.36 (mH, ), 7.47-7.66 (mH, ), 8.11 (sH, ), 8.20 (sH, )

MS (ES+) m/z 471 (M+1)

The following compounds were obtained according to a similar manner tothat of Preparation 262.

Preparation 263

(2E)-3-(6-{[(3S)-1-(4-Chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

NMR (DMSO-d₆, δ): 1.53 (3H, br), 1.69 (3H, br), 1.92 (1H, m), 2.19 (1H,m), 3.23-3.70 (4H, m), 3.80 (1H, m), 3.95 (1H, m), 4.36 (0.5H, m), 4.49(0.5H, m), 4.87 (1H, br), 6.22 (0.5H, d, J=16.1 Hz), 6.25 (0.5H, d,J=16.1 Hz), 6.52 (0.5H, d, J=8.8 Hz), 6.56 (0.5H, d, J=9.1 Hz), 7.36(2H, m), 7.47-7.66 (4H, m), 8.11 (1H, s), 8.20 (1H, s)

MS (ES+) m/z 471 (M+1)

Preparation 264

To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate (1.0 g) in dioxane(70 mL) was added palladium(II) acetate (88 mg),2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (231 mg), cesiumcarbonate (1.79 g), and (3R)-1-benzyl-3-pyrrolidinamine (760 mg). Themixture was heated at 90 for 24 hours. The resulting mixture was pouredinto sat NH4Cl aq solution and extracted with AcOEt. The organic layerwas washed with sat. NH₄Cl aq solution, water, and brine, and dried overNa₂SO₄. The solvent was removed in vacuo and residual brown oil waspurified by silica gel column chromatography eluted withchloroform:methanol=9:1 to give ethyl(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g)as pale yellow oil.

NMR (CDCl₃, δ): 1.32 (3H, t, J=7.0 Hz), 2.33 (1H, m), 2.44 (1H, m), 2.56(1H, m), 2.78 (2H, m), 3.63 (2H, s), 4.03 (1H, m), 4.23 (2H, q, J=7.0Hz), 4.26 (1H, m), 6.20 (1H, d, J=15.8 Hz), 6.52 (2H, d, J=8.8 Hz), 7.32(7H, m), 7.58 (1H, d, J=15.8 Hz)

MS (ES+) m/z 351 (M+1)

Preparation 265

To a solution of ethyl(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g)in MeOH (3 mL) and dioxane (3 mL) was added 1N NaOH aq solution (5.8mL), and the mixture was stirred at ambient temperature for 2 hours. Tothe mixture was added 1N NaOH aq solution (5.8 mL) and heated at 50° C.for 2 hours. The pH value of the mixture was adjusted to 7 with 1N HCl,and the solvent was removed in vacuo. Obtained solid was suspended intoluene and the residual water was geotropically removed to give(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid andthe crude product was used in next reaction without furtherpurification.

NMR (DMSO-d₆, δ): 1.65 (1H, br), 2.26 (1H, br), 2.74 (1H, br), 2.89 (1H,br), 3.43 (1H, br), 3.69 (1H, br), 3.97 (1H, br), 4.10 (0.5H, br), 4.37(0.5H, br), 6.14 (1H, d, J=15.8 Hz), 6.46 (1H, d, J=5.9 Hz), 6.55 (2H,d, J=8.4 Hz), 7.28 (1H, br), 7.37 (4H, m), 7.42 (1H, d, J=15.8 Hz), 7.04(1H, m)

MS (ES+) m/z 323 (M+1)

Preparation 266

To a solution of(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid (936mg, crude) in DMF (10 mL) was added was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (442 mg), HOBt (588 mg), andEDCI (676 mg) and the resulting mixture was stirred at ambienttemperature for 3 hours. The reaction mixture was diluted with water andextracted with AcOEt. The organic phase was washed with sat NH₄Cl aqsolution, sat NaHCO₃ aq solution, and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue was purified by preparativethin layer chromatography (chloroform:methanol=10:1) to give(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(945 mg) as pale yellow form.

NMR (CDCl₃, δ): 1.63 (3H, br), 1.85 (3H, br), 2.33 (1H, m), 2.45 (1H,m), 2.59 (1H, dd, J=9.9, 3.3 Hz), 2.80 (1H, m), 3.64 (2H, s), 2.64 (1H,m), 4.00 (1H, m), 4.00 (1H, m), 4.29 (1H, d, J=7.7 Hz), 4.99 (1H, s),6.26 (1H, br), 6.51 (1H, d, J=8.4 Hz), 7.27 (1H, m), 7.32 (6H, m), 7.62(1H, d, J=15.8 Hz),

MS (ES+) m/z 422 (M+1)

Preparation 267

To a solution of 3-methyl-2-pyridinamine (10 g) in a mixed solution ofAcOH (60 mL), water (12 mL), and sulfuric acid (4.2 mL) was addedperiodic acid dihydrate (4.22 g) and iodine (9.39 g), and the mixturewas heated at 80° C. for 2 hours. The reaction mixture was poured into5% Na₂S₂O₃ aq solution and extracted with ether. The organic layer waswashed with 1N NaOH aq solution and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo and obtained residual solid wasrecrystallized with EtOH to give 5-iodo-3-methyl-2-pyridinamine (9.00 g)as pale yellow powder.

NMR (CDCl₃, δ): 2.09 (3H, s), 4.95 (2H, br), 7.54 (1H, m), 8.03 (1H, m)

Preparation 268

To a suspension of 5-iodo-3-methyl-2-pyridinamine (7.0 g) in 47%hydrobromic acid was successively added bromine (2.31 mL) and aqsolution of NaNO₂ (5.16 g), the temperature being kept below 0° C.during addition. The reaction mixture was stirred for 1 hour at 5° C.and warmed to ambient temperature. The reaction was continued for 4hours at ambient temperature and the mixture was diluted with NaOH (18 gin water 150 mL) and extracted with AcOEt. The organic phase was washedwith 5% Na₂S₂O₃ aq solution, water, and brine, and dried over Na₂SO₄.The solvent was removed in vacuo, and the residue was purified by silicagel column chromatography eluted with chloroform to give2-bromo-5-iodo-3-methylpyridine (2.95 g) as pale yellow powder.

NMR (CDCl₃, δ): 2.36 (3H, s), 7.83 (1H, s), 8.41 (1H, s),

Preparation 269

To a solution of 2-bromo-5-iodo-3-methylpyridine (1.5 g) in DMF (15 mL)was added palladium(II) acetate (56.5 mg) and tri-o-tolylphosphine (230mg) and diisopropylethylamine (3.5 mL), and ethyl acrylate (1.09 mL).The mixture was heated at 90° C. for 1 hour. Resulting mixture waspoured into water and extracted with AcOEt. The organic layer was washedwith water and brine, and dried over Na₂SO₄, and the solvent was removedin vacuo. Residual brown oil was purified by silica gel columnchromatography eluted with AcOEt and hexane (1:4-1:2) to give ethyl(2E)-3-(6-bromo-5-methyl-3-pyridyl)acrylate (1.00 g) as pale yellowpowder.

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.0 Hz), 2.43 (3H, s), 4.29 (2H, q, J=7.0Hz), 6.50 (1H, d, J=16.1 Hz), 7.60 (1H, d, J=16.1 Hz), 7.66 (1H, m),8.33 (1H, m)

MS (ES+) m/z 270 (M+1)

Preparation 270

To a solution of ethyl (2E)-3-(6-bromo-5-methyl-3-pyridyl)acrylate (500mg) in dioxane (5 mL) was added palladium(II) acetate (41.6 mg) and2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (109 mg) andcesium carbonate (843 mg), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (359mg). The mixture was heated at 100° C. for 18 hours. The resultingmixture was poured into sat.NH₄Cl aqueous solution and extracted withAcOEt. The organic layer was washed with sat. NH₄Cl aq solution, water,and brine, and dried over Na₂SO₄. The solvent was removed in vacuo andresidual brown oil was purified by preparative thin layer chromatography(chloroform:methanol=90:10) to give ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate(366 mg) as pale yellow oil.

NMR (CDCl₃, δ): 1.32 (3H, t, J=7.0 Hz), 1.72 (1H, m), 2.10 (3H, s), 2.38(2H, m), 2.72 (2H, m), 2.95 (1H, m), 6.67 (2H, s), 4.24 (2H, q, J=7.0Hz), 4.72 (1H, m), 4.89 (1H, m), 6.20 (1H, d, J=16.1 Hz), 7.33 (5H, m),7.42 (1H, s), 7.56 (1H, d, J=16.1 Hz), 8.09 (1H, s)

MS (ES+) m/z 366 (M+1)

Preparation 271

To a solution of ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate(366 mg) in MeOH (2 mL) and dioxane (2 mL) was added 1N NaOH aq solution(2.0 mL), and the mixture was stirred at ambient temperature for 3hours. The pH value of the mixture was adjusted to 7 with 1N HCl, andthe solvent was removed in vacuo. Obtained solid was suspended intoluene and the residual water was geotropically removed to give(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylicacid and the crude product was used in next reaction without furtherpurification.

NMR (DMSO-d₆, δ): 1.92 (1H, br), 2.11 (3H, s), 2.26 (1H, br), 2.60-2.89(2H, br), 2.97-3.23 (2H, br), 3.85 (2H, br), 4.59 (1H, br), 6.25 (1H, d,J=16.1 Hz), 7.34 (5H, m), 7.43 (1H, d, J=16.1 Hz), 7.67 (1H, s), 8.08(1H, s)

MS (ES+) m/z 338 (M+1)

Preparation 272

To a solution of(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylicacid (338 mg, crude) in DMF (4 mL) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (153 mg), HOBt (203 mg), andEDCI (233 mg) and the resulting mixture was stirred at ambienttemperature for 3 hours. The reaction mixture was diluted with water andextracted with AcOEt. The organic phase was washed with sat NH₄Cl aqsolution, sat NaHCO₃ aq solution, and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue was purified by preparativethin layer chromatography (chloroform:methanol=90:10) to give(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(306 mg) as pale yellow form.

NMR (CDCl₃, δ): 1.67 (3H, br), 1.85 (3H, br), 2.10 (3H, s), 2.39 (2H,m), 2.72 (2H, m), 2.95 (1H, m), 3.65 (1H, m), 3.67 (2H, s), 4.72 (1H,m), 4.87 (1H, m), 5.00 (1H, br), 6.25 (1H, br), 7.33 (5H, m), 7.38 (1H,s), 7.61 (1H, d, J=16.1 Hz), 8.11 (1H, s)

MS (ES+){m/z 437 (M+1)

The following compound was obtained in a similar manner to that ofPreparation 274.

Preparation 273

tert-Butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-piperidinecarboxylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.43 (9H, s), 1.59-1.81(3H, m), 1.87-2.03 (1H, m), 3.30-3.47 (3H, m), 3.71 (1H, d, J=10 Hz),3.96 (1H, br peak), 4.25 (2H, q, J=7 Hz), 4.96 (1H, br peak), 6.70 (1H,d, J=15 Hz), 7.57 (1H, d, J=15 Hz), 7.91 (1H, d, J=2 Hz), 8.07 (1H, d,J=2 Hz)

MS (ES+) m/z 377

Preparation 274

Ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (4.70 g) and(3R)-1-(cyclohexylmethyl)-3-piperidinamine (4.77 g) were combined in1,4-dioxane (80 mL) at ambient temperature. To this solution were addedpalladium(II) acetate (248 mg) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(652 mg) at thesame temperature and the mixture was stirred for 5 minutes. To theresulting mixture was added cesium carbonate (10.1 g) and the mixturewas heated at 95° C. for twenty-four hours. The reaction mixture wasallowed to cool to ambient temperature and the insoluble solid wasfiltered off. The filtrate was concentrated in vacuo and the residue wasextracted with chloroform (300 mL). The chloroform phase was washed withsaturated sodium bicarbonate (100 mL) and brine (100 mL). The aqueouslayer was reextracted with chloroform (100 mL). The organic phase werecombined, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by a flash column chromatography eluting with agradient solvent system from EtOAc-Hexane (1:1 v/v) to EtOAc to affordethyl(2E)-3-(5-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate(4.80 g) as a yellow amorphous solid.

¹H-NMR (300 MHz, CDCl₃) δ 0.78-0.96 (mH, 2), 1.08-1.29 (3H, m), 1.33(3H, t, J=7.3 Hz), 1.41-1.85 (10H, m), 2.04-2.19 (3H, m), 2.35-2.46 (1H,m), 2.51-2.69 (2H, m), 4.04-4.15 (1H, m), 4.25 (2H, q, J=7.3 Hz), 5.63(1H, br.s), 6.67 (1H, d, J=15.4 Hz), 7.58 (1H, d, J=15.4 Hz), 7.89 (1H,d, J=1.1 Hz), 8.05 (1H, d, J=1.1 Hz)

MS (ES+) m/z 373(M+1)

Preparation 275

To a solution of ethyl(2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl)acrylate dihydrochloride(300 mg) in 1,2-dichloroethane (5 mL) were added diisopropylethylamine(222 mg) and cyclohexanone (93 mg), and the mixture was stirred atambient temperature for 5 min. To the mixture was added sodiumtriacetoxybrohydryde (364 mg) and stirred for 4 hrs, and resultingmixture was poured into saturated sodium bicarbonate solution, andextracted with chloroform. The organic layer was washed with water, andbrine, and dried over magnesium sulfate. The solvent was removed invacuo and the residue was purified by preparative thin layerchromatography (chloroform-MeOH=10-1) to give ethyl(2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate(235 mg) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 0.96-1.36 (9H, m), 1.49-1.88 (8H, m),2.24-2.38 (1H, m), 2.38-2.51 (1H, m), 2.57-2.75 (3H, m), 4.06 (1H, brpeak), 4.25 (2H, q, J=7 Hz), 5.69 (1H, br peak), 6.66 (1H, d, J=15 Hz),7.56 (1H, d, J=15 Hz), 7.90 (1H, d, J=2 Hz), 8.05 (1H, d, 3=2 Hz)

MS (ES+) m/z 359

The following compounds were obtained in a similar manner to that ofPreparation 275.

Preparation 276

tert-Butyl [(3R)-1-(cyclohexylmethyl)-3-piperidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 0.73-0.92 (2H, m), 1.08-1.31 (3H, m),1.35-1.82 (10H, m), 1.45 (9H, s), 1.98-2.51 (6H, m), 3.65-3.80 (1H, m),4.91-5.11 (1H, m)

MS (ES+) m/z 297(M+1)

Preparation 277

Ethyl(2E)-3-(5-{[(3R)-1-(4-methylbenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.50-1.84 (4H, m),2.10-2.30 (1H, m), 2.34 (3H, s), 2.40-2.74 (3H, m), 3.44 (1H, d, J=12Hz), 3.53 (1H, d, J=12 Hz), 4.10 (1H, br peak), 4.25 (2H, q, J=7 Hz),5.57 (1H, br peak), 6.67 (1H, d, J=15 Hz), 7.14 (2H, d, J=8 Hz), 7.20(2H, d, J=8 Hz), 7.56 (1H, d, J=15 Hz), 7.89 (1H, d, J=2 Hz), 8.04 (1H,d, J=2 Hz)

MS (ES+) m/z 381

Preparation 278

Ethyl(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.40-1.85 (4H, m),2.15-2.32 (1H, m), 2.45-2.65 (3H, m), 3.44 (1H, d, J=12 Hz), 3.51 (1H,d, J=12 Hz), 4.10 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.45 (1H, brpeak), 6.65 (1H, d, J=15 Hz), 7.16-7.32 (4H, m), 7.56 (1H, d, J=15 Hz),7.89 (1H, s), 8.04 (1H, s)

MS (ES+) m/z 401

Preparation 279

Ethyl(2E)-3-(5-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.21-1.93 (14H, m), 2.20-2.39 (1H, m),2.47-2.76 (4H, m), 4.09 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.58 (1H,br peak), 6.68 (1H, d, J=15 Hz), 7.58 (1H, d, J=15 Hz), 7.93 (1H, s),8.06 (1H, s)

MS (ES+) m/z 345

Preparation 280

Ethyl(2E)-3-(5-{[(3R)-1-(cyclopentylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.11-1.29 (2H, m), 1.22 (3H, t, J=7 Hz),1.45-1.65 (6H, m), 1.65-1.85 (4H, m), 1.97-2.30 (4H, m), 2.36-2.50 (1H,m), 2.58-2.77 (2H, m), 4.10 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.66(1H, br peak), 6.66 (1H, d, J=15 Hz), 7.58 (1H, d, J=15 Hz), 7.90 (1H,s), 8.05 (1H, s)

MS (ES+) m/z 359

Preparation 281

To a solution of mixture of ethyl(2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate(227 mg) in EtOH (2 mL) was added 1N sodium hydroxide solution (1.3 mL)at ambient temperature and the mixture was allowed to stand for 18 hrs.The reaction mixture was adjusted to pH 6.0 with 1 mol/L hydrochloricacid and evaporated in vacuo. The residue was dissolved in a mixture ofchloroform and MeOH (5-1) and the precipitate was filtered off. Thefiltrate was concentrated in vacuo to give(2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid (209 mg) as a solid.

¹H-NMR (300 MHz, DMSO-d₆) δ 0.96-1.49 (6H, m), 1.49-1.64 (2H, m),1.64-2.00 (6H, m), 2.50-3.60 (5H, m), 4.04 (1H, br peak), 6.46 (1H, d,J=15 Hz), 7.49 (1H, d, J=15 Hz), 7.48 (1H, br peak), 8.01 (1H, s), 8.21(1H, s)

The following compounds were obtained in a similar manner to that ofPreparation 281.

Preparation 282

(2E)-3-(5-{[(3R)-1-Benzyl-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid

¹H-NMR (300 MHz, DMSO-d₆) δ 1.15-1.45 (1H, m), 1.45-2.20 (3H, m),2.55-3.07 (2H, m), 3.40-3.50 (2H, m), 4.25-4.42 (3H, m), 6.46 (1H, d,J=15 Hz), 7.16-7.54 (6H, m), 8.00 (1H, s), 8.16 (1H, s)

MS (ES+) m/z 339

Preparation 283

(2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 0.74-0.94 (2H, m), 1.04-1.30 (3H, m), 1.41(1H, m), 1.52-1.82 (6H, m), 2.11-2.31 (3H, m), 2.34-2.47 (2H, m),2.52-2.80 (2H, m), 4.30 (1H, m), 6.45 (1H, d, J=15.5 Hz), 7.47 (1H, d,J=15.5 Hz), 7.85 (1H, d, J=6.6 Hz), 8.00 (1H, s), 8.19 (1H, s)

MS (ES+) m/z 331

Preparation 284

(2E)-3-(5-{[(3R)-1-(4-Methylbenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 1.30-1.54 (1H, m), 1.69-2.15 (3H, m), 2.33(3H, s), 2.44-3.05 (2H, m), 3.21-3.56 (2H, m), 4.20-4.40 (3H, m), 6.50(1H, d, J=15 Hz), 7.28 (2H, d, J=8 Hz), 7.44 (2H, d, J=8 Hz), 7.51 (1H,d, J=15 Hz), 7.86 (1H, d, J=8 Hz), 8.01 (1H, s), 8.21 (1H, s)

MS (ES+) m/z 353

Preparation 285

(2E)-3-(5-{[(3R)-1-(4-Chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 1.35-1.65 (1H, m), 1.65-2.14 (3H, m),2.56-2.75 (1H, m), 2.75-2.95 (1H, m), 3.25-3.59 (2H, m), 4.16-4.49 (3H,m), 6.50 (1H, d, J=15 Hz), 7.45-7.70 (5H, m), 7.85 (1H, d, J=8 Hz), 8.01(1H, s), 8.22 (1H, s)

MS (ES+){m/z 373

Preparation 286

A mixture of(2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid (209 mg), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (89 mg), HOBt(111 μg) and EDCI (158 mg) in DMF (4.5 mL) was stirred at 0° C. for 1 hrand the mixture was stirred at ambient temperature for 18 hrs. Thereaction mixture was evaporated in vacuo and the residue was partitionedbetween saturated sodium bicarbonate solution and EtOAc. The organiclayer was separated, washed water and brine, dried over magnesiumsulfate, and evaporated in vacuo. The residue was purified by silica gelcolumn chromatography (chloroform-MeOH=95-5) to give(2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(198 mg) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 0.91-1.35 (6H, m), 1.35-1.95 (13H, m),2.20-2.38 (1H, m), 2.38-2.53 (1H, m), 2.53-2.74 (3H, m), 3.59-3.70 (1H,m), 3.90-4.02 (1H, m), 4.02-4.14 (1H, m), 5.01 (1H, br s), 5.60-5.75(1H, m), 6.65 (1H, br peak), 7.63 (1H, d, J=15 Hz), 7.88 (1H, s), 8.04(1H, s), 8.31 (1H, br peak)

MS (ES+) m/z 430

The following compounds were obtained in a similar manner to that ofPreparation 286.

Preparation 287

(2E)-3-(5-{[(3R)-1-Benzyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.35-1.96 (9H, m), 2.14-2.35 (1H, m),2.40-2.70 (3H, m), 3.49 (1H, d, J=13 Hz), 3.55 (1H, d, J=13 Hz),3.60-3.78 (1H, m), 3.86-4.03 (1H, m), 4.03-4.15 (1H, m), 4.94-5.05 (1H,m), 5.45-5.60 (1H, m), 6.65 (1H, br peak), 7.15-7.35 (5H, m), 7.62 (1H,d, J=15 Hz), 7.86 (1H, s), 8.01 (1H, s), 8.19-8.35 (1H, m)

Preparation 288

(2E)-3-(5-{[(3R)-1-(4-Methylbenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.45-1.96 (9H, m), 2.11-2.29 (1H, m), 2.34(3H, s), 2.43-2.72 (3H, m), 3.43 (1H, d, J=12 Hz), 3.52 (1H, d, J=12Hz), 3.59-3.71 (1H, m), 3.90-4.04 (1H, m), 4.04 (1H, br peak), 5.01 (1H,br s), 5.58 (1H, br peak), 6.66 (1H, br peak), 7.14 (2H, d, J=8 Hz),7.19 (2H, d, J=8 Hz), 7.61 (1H, d, j=15 Hz), 7.87 (1H, s), 8.00 (1H, s),8.35 (1H, br peak)

MS (ES+) m/z 452

Preparation 289

(2E)-3-(5-{[(3R)-1-(4-Chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.56-1.95 (9H, m), 2.15-2.33 (1H, m),2.43-2.66 (3H, m), 3.44 (1H, d, J=12 Hz), 3.50 (1H, d, J=12 Hz),3.59-3.71 (1H, m), 3.86-4.04 (1H, m), 4.10 (1H, br peak), 5.00 (1H, brs), 5.48 (1H, br peak), 6.70 (1H, br peak), 7.19-7.35 (4H, m), 7.53 (1H,d, J=15 Hz), 7.86 (1H, s), 8.01 (1H, s), 8.35 (1H, br peak)

MS (ES+) m/z 472

Preparation 290

(2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d₆) δ 0.73-0.93 (2H, m), 1.06-1.28 (3H, m),1.30-1.83 (13H, m), 2.10-2.30 (3H, m), 2.31-2.44 (2H, m), 2.61 (1H, m),2.72 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.29 (1H, m), 4.89 (1H, m),6.60 (1H, d, J=15.2 Hz), 7.38 (1H, d, J=15.2 Hz), 7.73 (1H, d, J=6.6Hz), 7.98 (1H, s), 8.11 (1H, s), 11.18 (1H, s)

MS (ES+) m/z 430

Preparation 291

To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (4.0 g) and1-(chloromethyl)-4-methylbenzene (3.17 g) in DMF (40 mL) was addedN-ethyl-N-isopropyl-2-propanamine (5.55 g) at ambient temperature andthe resulting mixture was heated at 70 for four hours. The mixture wasallowed to cool to ambient temperature and extracted with ethyl acetate(100 mL). The organic phase was washed with water (50 mL) and brine (50mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by a flashchromatography etluting with gradient solvent system (ethylacetate-hexane from 1:4 v/v to 1:1 v/v) to give tert-butyl[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.69 g) as a paleyellow syrup.

¹H-NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 1.49-1.64 (1H, m), 2.12-2.37(2H, m), 2.34 (3H, s), 2.43-2.64 (2H, m), 2.68-2.84 (1H, m), 3.55 (2H,s), 4.07-4.23 (1H, m), 4.76-4.92 (1H, m), 7.12 (2H, d, J=8.1 Hz), 7.19(2H, d, J=8.1 Hz)

MS (ES+) m/z 291(M+1)

The following compounds were obtained in a similar manner to that ofPreparation 291.

Preparation 292

tert-Butyl [(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 0.75-0.95 (2H, m), 1.06-1.31 (3H, m), 1.44(3×3H, s), 1.50-1.83 (7H, m), 2.11-2.30 (4H, m), 2.39-2.58 (2H, m), 2.73(1H, m), 4.13 (1H, m), 4.82 (1H, m)

MS (ES+) m/z 283

Preparation 293

To a stirred solution of tert-butyl[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.6 g) in ethylacetate (10 mL) was added 4N hydrogen chloride in ethyl acetate (60 mL)at ambient temperature and the resulting mixture was stirred at the sametemperature for three hours. The mixture was concentrated in vacuo andthe residual syrup was dissolved in chloroform (100 mL). To thissolution was added saturated sodium bicarbonate (50 mL) and theresulting biphasic mixture was vigorously stirred at ambient temperaturefor half an hour. The organic layer was separated and the aqueous layerwas reextracted with chloroform (50 mL) two times. The combined organiclayer was dried over anhydrous sodium sulfate and evaporated in vacuo toafford (3R)-1-(4-methylbenzyl)-3-pyrrolidinamine (2.1 g) as a pale brownviscous oil, which was used in the next step without furtherpurification.

¹H-NMR (300 MHz, CDCl₃) δ 1.43-1.57 (1H, m), 1.81 (2H, br.s), 2.12-2.37(1H, m), 2.28-2.37 (1H, m), 2.34 (3H, s), 2.43-2.55 (1H, m), 2.67-2.79(2H, m), 3.46-3.55 (1H, m), 3.56 (1H, d, J=12.8 Hz), 3.62 (1H, d, J=12.8Hz), 7.12 (2H, d, J=7.7 Hz), 7.22 (2H, d, J=7.7 Hz)

MS (ES+) m/z 191(M+1)

The following compound was obtained in a similar manner to that ofPreparation 293.

Preparation 294

(3R)-1-(Cyclohexylmethyl)-3-pyrrolidinamine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 0.83-1.03 (2H, m), 1.04-1.34 (3H, m),1.52-1.77 (4H, m), 1.77-1.97 (2H, m), 2.12 (1H, m), 2.39 (1H, m),2.95-3.26 (3H, m), 3.28-4.09 (4H, m), 8.65 (2H, br)

MS (ES+) m/z 183

Preparation 295

To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg)and potassium carbonate (4.94 mg) in DMF (15 mL) was added(3R)-1-benzyl-3-piperidinamine dihydrochloride (668 mg) under nitrogenat ambient temperature and the mixture was stirred at 85° C. for 18 hrs.The reaction mixture was evaporated in vacuo and the residue waspartitioned between water and ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (chloroform-MeOH=97-3) to give ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (125mg) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.47-1.83 (3H, m),2.16-2.33 (1H, m), 2.42-2.73 (3H, m), 3.49 (1H, d, J=13.0 Hz), 3.56 (1H,d, J=13.0 Hz), 4.06-4.17 (1H, m), 4.25 (2H, q, J=7.1 Hz), 5.55 (1H, brpeak), 6.67 (1H, d, J=15.5 Hz), 7.23-7.38 (5H, m), 7.57 (1H, d, J=15.5Hz), 7.89 (1H, d, J=1.3 Hz), 8.04 (1H, d, J=1.3 Hz)

MS (ES+) m/z 367

The following compound was obtained in a similar manner to that ofPreparation 295.

Preparation 296

Ethyl(2E)-3-(5-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.80-0.98 (2H, m), 1.08-1.31 (3H, m), 1.33(3H, t, J=7 Hz), 1.44 (1H, m), 1.57-1.85 (6H, m), 2.18-2.42 (4H, m),2.54-2.69 (2H, m), 2.88 (1H, m), 4.25 (2H, q, J=7 Hz), 4.43 (1H, m),5.23 (1H, d, J=8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.57 (1H, d, J=15.5 Hz),7.89 (1H, s), 8.06 (1H, s)

MS (ES+) m/z 359

Preparation 297

To a solution of tert-butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-piperidinecarboxylate(6.26 g) in a mixture of 1,4-dioxane (25 mL) and MeOH (5 mL) was added4N hydrogen chloride solution in ethyl acetate (30 mL) in water bath.

The mixture was stirred at same temperature for 3 hrs. After evaporationof solvent, the residue was triturated with isopropylether to give ethyl(2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride(5.8 g) as an amorphous powder.

¹H-NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7 Hz), 1.46-1.65 (1H, m),1.65-1.85 (1H, m), 1.85-2.06 (3H, m), 2.66-3.00 (2H, m), 3.05-3.25 (1H,m), 3.25-3.41 (1H, m), 4.18 (2H, q, J=7 Hz), 6.54 (1H, d, J=15 Hz), 7.57(1H, d, J=15 Hz), 7.95-8.19 (2H, m), 8.28 (1H, s), 9.14 (2H, br peak)

MS (ES+) m/z 277

The following compound was obtained in a similar manner to that ofPreparation 297.

Preparation 298

(3R)-1-(Cyclohexylmethyl)-3-piperidinamine

¹H-NMR (300 MHz, CDCl₃) δ 0.75-0.92 (2H, m), 1.02-1.31 (4H, m),1.31-1.61 (4H, m), 1.60-1.87 (8H, m), 1.92-2.07 (1H, m), 2.08 (2H, d,J=7.2 Hz), 2.46-2.58 (1H, m), 2.62-2.73 (1H, m), 2.80-2.92 (1H, m)

MS (ES+) m/z 197(M+1)

Preparation 299

To a solution of (5-chloro-2-pyrazinyl)methanol (11.0 g) in dioxane(carbethoxymethylene)triphenylphosphorane (29.2 g). After stirring for 2hours at room temperature, a resulting precipitate was filtered and thefiltrate was evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give ethyl(2E)-3-(5-chloro-2-pyrazinyl)acrylate (11.0 g).

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz),7.01 (1H, d, J=15 Hz), 7.66 (1H, d, J=15 Hz), 8.43 (1H, s), 8.60 (1H, s)

Preparation 300

To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.50 g) inDMF (21 mL) was added (3R)-1-benzyl-3-pyrrolidinamine (2.24 g) and Et₃N(3.44 mL). After stirring for 3 hours at 100° C., the reaction mixturewas partitioned between ethyl acetate and H₂O. The organic layer waswashed with brine, dried over MgSO₄, filtered, and evaporated in vacuo.The residue was purified by column chromatography on silica gel to giveethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(1.15 g)

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.65-1.76 (1H, m),2.32-2.43 (2H, m), 2.66-2.70 (2H, m), 2.87-2.95 (1H, m), 3.62-3.66 (2H,m), 4.25 (2H, q, J=7 Hz), 4.40-4.52 (1H, m), 5.21 (1H, d, J=8 Hz), 6.67(1H, d, J=15 Hz), 7.24-7.35 (5H, m), 7.57 (1H, d, J=15 Hz), 7.87 (1H,s), 8.05 (1H, s)

MS (ES+) m/z 353 (M+1)

Preparation 301

To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.78 g)and (3R)-1-(4-chlorobenzyl)-3-pyrrolidinamine (2.65 g) in DMF (25 mL)was added K₂CO₃ (5.79 g). After stirring for 3 hours at 100° C., thereaction mixture was partitioned between ethyl acetate and H₂O. Theorganic layer was washed with H₂O, dried over MgSO₄, filtered, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to give ethyl(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(1.58 g).

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.66-1.74 (1H, m),2.31-2.43 (2H, m), 2.62-2.71 (2H, m), 2.85-2.92 (1H, m), 3.59-3.62 (2H,m), 4.25 (2H, q, J=7 Hz), 4.41-4.52 (1H, m), 5.19 (1H, d, J=8 Hz), 6.68(1H, d, J=0.15 Hz), 7.23-7.32 (4H, m), 7.57 (1H, d, J=15 Hz), 7.88 (1H,s), 8.05 (1H, s)

MS (ES+) m/z 387 (M+1)

The following compound was obtained in a similar manner to that ofPreparation 301.

Preparation 302

Ethyl(2E)-3-(5-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.67-1.73 (1H, m),2.32-2.42 (2H, m), 2.34 (3H, s), 2.66-2.69 (2H, m), 2.88-2.95 (1H, m),3.60-3.63 (2H, m), 4.25 (2H, q, J=7 Hz), 4.41-4.51 (1H, m), 5.24-5.31(1H, m), 6.67 (1H, d, J=15 Hz), 7.13 (2H, d, J=8 Hz), 7.21 (2H, d, J=8Hz), 7.57 (1H, d, J=15 Hz), 7.87 (1H, s), 8.05 (1H, s)

MS (ES+) m/z 367 (M+1)

Preparation 303

1) To a solution of ethyl(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(1.57 g) in dioxane (20 mL) was added 1N sodium hydroxide (12.2 mL).After stirring at 60° C. for 2 hours, the reaction mixture was added H₂O(100 mL) and acidified with 1N hydrochloric acid (to pH 4). A resultingmixture was evaporated in vacuo

2) To a mixture of above product,O-tetrahydro-2H-pyran-2-ylhydroxylamine (713 mg), and1-hydroxybenzotriazole (823 mg) in N,N-dimethylformamide (20 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (945 mg) at 4° C.The mixture was warmed to ambient temperature and stirred for 8 hours.The reaction mixture was added saturated NaHCO₃ (20 mL) and water (80mL), and extracted with ethyl acetate. The organic layer was dried overMgSO₄, filtered, and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel to give(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(1.44 g).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.47-1.74 (7H, m), 2.16-2.30 (1H, m),2.37-2.45 (2H, m), 2.61-2.80 (2H, m), 3.48-3.60 (3H, m), 3.89-4.00 (1H,m), 4.25-4.35 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=15 Hz), 7.32-7.42(5H, m), 7.77 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.2 (1H,brs)

MS (ES+) m/z 458 (M+1)

The following compounds were obtained in a similar manner to that ofPreparation 303.

Preparation 304

(2E)-3-(5-{[(3R)-1-Cyclopentyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.20-1.96 (20H, m), 2.20-2.37 (1H, m),2.47-2.80 (4H, m), 3.59-3.71 (1H, m), 3.88-4.02 (1H, m), 4.02-4.15 (1H,m), 5.02 (1H, br s), 5.56 (1H, br peak), 6.68 (1H, br peak), 7.63 (1H,d, J=15 Hz), 7.90 (1H, s), 8.02 (1H, s), 8.30 (1H, br peak)

MS (ES+) m/z 416

Preparation 305

(2E)-3-(5-{[(3R)-1-(Cyclopentylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.11-1.30 (2H, m), 1.45-1.98 (16H, m),1.96-2.29 (4H, m), 2.35-2.51 (1H, m), 2.56-2.76 (2H, m), 3.59-3.70 (1H,m), 3.90-4.03 (1H, m), 4.10 (1H, br peak), 5.01 (1H, br s), 5.65 (1H, brpeak), 6.67 (1H, br peak), 7.62 (1H, d, J=15 Hz), 7.87 (1H, s), 8.03(1H, s), 8.34 (1H, br peak)

MS (ES+) m/z 430

Preparation 306

(2E)-3-(5-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d₆) δ 1.47-1.74 (7H, m), 2.16-2.30 (1H, m),2.36-2.46 (2H, m), 2.60-2.80 (2H, m), 3.47-3.60 (3H, m), 3.88-4.00 (1H,m), 4.25-4.35 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=15 Hz), 7.21-7.34(5H, m), 7.37 (1H, d, J=15 Hz), 7.77 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09(1H, s), 11.2 (1H, brs)

MS (ES+) m/z 424 (M+1)

Preparation 307

(2E)-3-(5-{[(3R)-1-(4-Methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d₆) δ 1.47-1.74 (7H, m), 2.15-2.30 (1H, m), 2.27(3H, s), 2.34-2.45 (2H, m), 2.60-2.77 (2H, m), 3.47-3.57 (3H, m),3.89-4.01 (1H, m), 4.24-4.36 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=15Hz), 7.11 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz), 7.37 (1H, d, J=15 Hz),7.76 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.2 (1H, brs)

MS (ES+) m/z 438 (M+1)

The following compound was obtained in similar manners to those ofPreparations 281 and 286.

Preparation 308

(2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d₆) δ 0.70-0.91 (2H, m), 1.02-1.32 (3H, m),1.36-2.00 (16H, m), 2.02-2.11 (2H, m), 2.44-2.5.5 (2H, m), 2.56-2.67(1H, m), 2.75-2.86 (1H, m), 3.46-3.58 (1H, m), 3.82-4.03 (2H, m), 4.89(1H, br.s), 6.59 (1H, d, J=15.4 Hz), 7.38 (1H, d, J=15.4 Hz), 7.43 (1H,br.s), 7.97 (1H, s), 8.11 (1H, s)

MS (ES+) m/z 444(M+1)

Preparation 309

To a solution of 5,6-dichloronicotinic acid (7.0 g, 35 mmol) in DMF wereadded iodoethane (6.0 g, 38.5 mmol) and K₂CO₃ (5.8 g, 42 mmol) atambient temperature and the mixture was stirred at 45° C. for 5 hrs. Tothe reaction mixture were added (3R)-1-benzyl-3-piperidinaminedihydrochloride (10.1 g, 38.5 mmol) and K₂CO₃ (16.9 g, 122 mmol) and thereaction mixture was stirred at 90° C. for 18 hrs. The reaction mixturewas evaporated in vacuo and the residue was partitioned between waterand EtOAc. The organic layer was separated, washed water and brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc-hexane/1-4˜1-3) togive ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate(6.75 g, 52%) as a powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7.1 Hz), 1.51-1.69 (2H, m),1.69-1.88 (2H, m), 2.18-2.33 (1H, m), 2.41-2.54 (1H, m), 2.54-2.67 (1H,m), 2.67-2.79 (1H, m), 3.45 (1H, d, J=13 Hz), 3.61 (1H, d, J=13 Hz),4.32 (2H, q, J=7.1 Hz), 6.24 (1H, br peak), 7.21-7.41 (5H, m), 8.00 (1H,d, J=2 Hz), 8.65 (1H, d, J=2 Hz);

MS (ES+) m/z 374.

Preparation 310

A mixture of ethyl (2E)-3-(5-bromo-2-pyridinyl}acrylate (480 mg),(3R)-1-benzyl-3-pyrrolidinamine (363 mg), cesium carbonate (855 mg, 1.4eq.), CyDMABP (2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,63 mg, 0.15 eq.), and palladium acetate (250 mg, 0.6 eq.) in dioxane (25ml) was stirred at 100° C. for 2 days.

Water and ethyl acetate was added and aqueous layer was separated.

Aqueous layer was extracted with ethyl acetate (twice).

Combined organic layer was washed with water and brine, dried overMgSO₄, filtered and evaporated.

The residue was column chromatographed on silica gel to give 37 mg (6%)of ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl}acrylate asan oil.

MASS (ESI+): m/z=352.3 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.31 (3H, t, J=7.1 Hz), 1.68-1.78 (1H, m),2.31-2.95 (5H, m), 3.69 (2H, s), 4.01-4.09 (1H, m), 4.24 (2H, q, J=7.1Hz), 4.44-4.51 (1H, m), 6.62 (1H, d, J=15.5 Hz), 6.79 (1H, dd, J=8.5 and2.9 Hz), 7.23-7.36 (6H, m), 7.18 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.5Hz), 7.32-7.40 (5H, m), 7.60 (1H, d, J=15.5 Hz), 8.01 (1H, d, J=2.9 Hz).

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylatedihydrochloride (220 mg, 0.51 mmol) in 1,2-dichloroethane (4 mL) wereadded diisopropylethylamine (131 mg, 1.01 mmol) andcyclopentanecarboxaldehyde (52 mg, 0.53 mmol), and the mixture wasstirred at ambient temperature for 5 min. To the mixture was addedsodium triacetoxyborohydride (215 mg, 1.01 mmol) and stirred for 2 hrs,and resulting mixture was poured into saturated sodium bicarbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith water, and brine, and dried over magnesium sulfate. The solvent wasremoved in vacuo and the residue was purified by preparative thin layerchromatography (chloroform-MeOH=10-1) to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(225 mg, 100%) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.00-1.21 (2H, m), 1.36 (3H, t, J=7.5 Hz),1.46 (9H, s), 1.48-1.80 (8H, m), 1.80-2.10 (2H, m), 2.10-2.44 (2H, m),2.44-2.80 (2H, m), 2.90-3.06 (1H, m), 4.29 (2H, q, J=7.5 Hz), 4.80-4.96(1H, m), 6.46 (1H, d, J=15 Hz), 7.32 (1H, d, J=8 Hz), 7.66 (1H, d, J=15Hz), 7.80 (1H, dd, J=8, 2 Hz), 8.55 (1H, d, J=2 Hz);

MS (ES+) m/z 444.

The following compounds were obtained in a similar manner to that ofPreparation 311.

Preparation 312

ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7.1 Hz), 1.46-1.84 (5H, m),2.20-2.40 (1H, m), 2.40-2.67 (2H, m), 3.45-3.58 (2H, m), 3.97 (1H, brpeak), 4.32 (2H, q, J=7.1 Hz), 5.54 (1H, br peak), 6.33 (1H, d, J=8.7Hz), 7.23-7.40 (5H, m), 7.96 (1H, dd, J=8.8, 2.2 Hz), 8.73 (1H, d, J=2.2Hz);

MS (ES+) m/z 340.

Preparation 313

ethyl 6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate

¹H-NMR (300 MHz, CDCl3) δ 0.77-0.97 (2H, m), 1.05-1.30 (3H, m), 1.36(3H, t, J=7.1 Hz), 1.40-1.86 (10H, m), 1.97-2.25 (3H, m), 2.37-2.64 (3H,m), 3.84-4.08 (1H, m), 4.30 (2H, q, J=7.1 Hz), 5.59 (1H, br peak), 6.35(1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.6, 2.0 Hz), 8.74 (1H, d, J=2.0 Hz).

Preparation 314

ethyl(2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.46-1.84 (3H, m),2.18-2.36 (1H, m), 2.36-2.66 (3H, m), 3.43 (1H, d, J=13.5 Hz), 3.50 (1H,d, J=13.5 Hz), 3.88-4.04 (1H, m), 4.24 (2H, q, J=7.1 Hz), 5.21-5.41 (1H,m), 6.20 (1H, d, J=15.9 Hz), 6.38 (1H, d, J=8.8 Hz), 7.18-7.38 (4H, m),7.56 (1H, d, J=16.1 Hz), 7.60 (1H, dd, J=9.4, 2.3 Hz), 8.18 (1H, d,J=2.3 Hz); MS (ES+) m/z 400.

Preparation 315

ethyl(2E)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl}acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.16-1.90 (15H, m), 2.20-2.77 (5H, m), 3.92(1H, br peak), 4.24 (2H, q, J=7.1 Hz), 5.40 (1H, br peak), 6.20 (1H, d,J=15.9 Hz), 6.40 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=15.9 Hz), 7.61 (1H,dd, J=8.7, 2.3 Hz), 8.18 (1H, d, J=2.1 Hz);

MS (ES+) m/z 344.

Preparation 316

ethyl(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.06-1.33 (6H, m), 1.38 (3H, t, J=7.1 Hz),1.44-1.84 (3H, m), 1.84-2.00 (2H, m), 2.00-2.15 (1H, m), 2.25-2.56 (2H,m), 2.68-2.89 (2H, m), 2.89-3.05 (1H, m), 4.23-4.45 (3H, m), 5.24 (1H,br peak), 6.40 (1H, d, J=8.8 Hz), 6.81 (1H, d, J=36.3 Hz), 7.82 (1H, dd,J=8.8, 1.9 Hz), 8.24 (1H, s);

MS (ES+) m/z 362.

Preparation 317

ethyl(2E)-3-{6-[[(3R)-1-(1-adamantylmethyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridinyl}acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7.1 Hz), 1.44 (9H, s),1.50-2.30 (20H, m), 2.65-3.20 (1H, m), 4.29 (2H, q, J=7.2 Hz), 6.46 (1H,d, J=16.1 Hz), 8.31 (1H, d, J=8.2 Hz), 7.66 (1H, d, J=16.5 Hz), 7.81(1H, dd, J=8.3, 2.7 Hz), 8.56 (1H, d, J=2.7 Hz);

MS (ES+) m/z 510.

Preparation 318

ethyl(2E)-3-(6-{[(3R)-1-(4-methylbenzyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.47-1.84 (4H, m),2.18-2.37 (4H, m), 2.40-2.70 (3H, m), 3.44 (1H, d, J=13.1 Hz), 3.50 (1H,d, J=13.1 Hz), 3.95 (1H, br peak), 4.24 (2H, q, J=7.1 Hz), 5.40 (1H, brpeak), 6.20 (1H, d, J=15.9 Hz), 6.38 (1H, d, J=8.8 Hz), 7.12 (2H, d,J=7.9 Hz), 7.20 (2H, d, J=7.9 Hz), 7.55 (1H, d, J=15.5 Hz), 7.60 (1H,dd, J=8.8, 2.2 Hz), 8.17 (1H, d, J=2.1 Hz).

Preparation 319

ethyl(2Z)-2-fluoro-3-(6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7.1 Hz), 1.59-1.78 (1H, m),2.26-2.47 (5H, m), 2.60 (1H, dd, J=9.6, 3.2 Hz), 2.74 (1H, dd, J=9.7,6.4 Hz), 2.78-2.90 (1H, m), 3.56 (1H, d, J=12.8 Hz), 3.64 (1H, d, J=12.8Hz), 4.25-4.41 (3H, m), 5.12 (1H, br d, J=7.8 Hz), 6.38 (1H, d, J=8.9Hz), 6.79 (1H, d, J=36.2 Hz), 7.12 (2H, d, J=7.9 Hz), 7.21 (2H, d, J=7.9Hz), 7.81 (1H, dd, J=8.9, 2.2 Hz), 8.23 (1H, d, J=1.8 Hz);

MS (ES+) m/z 384.

Preparation 320

ethyl(2Z)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7.1 Hz), 1.56-1.78 (1H, m),2.28-2.46 (2H, m), 2.60 (1H, dd, J=9.7, 3.2 Hz), 2.73 (1H, dd, J=9.7,6.3 Hz), 2.77-2.88 (1H, m), 3.56 (1H, d, J=13.6 Hz), 3.61 (1H, d, J=13.6Hz), 4.26-4.42 (3H, m), 5.08 (1H, br d, J=7.9 Hz), 6.38 (1H, d, J=8.8Hz), 6.80 (1H, d, J=36.2 Hz), 7.25 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.7Hz), 7.82 (1H, dd, J=8.9, 2.2 Hz), 8.24 (1H, d, J=2.0 Hz).

Preparation 321

ethyl(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.5-1.85 (4H, m),2.20-2.35 (1H, m), 2.49-2.71 (3H, m), 3.46 (1H, d, J=13.5 Hz), 3.53 (1H,d, J=13.5 Hz), 4.12 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.50 (1H, brpeak), 6.67 (1H, d, J=15.5 Hz), 7.15-7.40 (4H, m), 7.58 (1H, d, J=15.5Hz), 7.91 (1H, s), 8.05 (1H, s);

MS (ES+) m/z 401.

Preparation 322

ethyl(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.48-1.88 (4H, m),2.20-2.36 (1H, m), 2.54-2.80 (3H, m), 3.56 (1H, d, J=13.6 Hz), 3.64 (1H,d, J=13.6 Hz), 4.14 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.72 (1H, brpeak), 6.66 (1H, d, J=1-5.5 Hz), 7.16-7.25 (2H, m), 7.34-7.42 (2H, m),7.56 (1H, d, J=15.5 Hz), 7.89 (1H, s), 8.03 (1H, s);

MS (ES+) m/z 401.

Preparation 323

ethyl(2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.50-1.82 (4H, m),2.18-2.31 (1H, m), 2.44-2.66 (3H, m), 3.45 (1H, d, J=13.2 Hz), 3.51 (1H,d, J=13.1 Hz), 4.10 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.46 (1H, brpeak), 6.67 (1H, d, J=15.6 Hz), 7.01 (2H, t, J=8.7 Hz), 7.21-7.33 (2H,m), 7.56 (1H, d, J=15.6 Hz), 7.90 (1H, s), 8.03 (1H, s);

MS (ES+) m/z 385.

Preparation 324

ethyl(2E)-3-(5-{[(3R)-1-(2-thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.50-1.69 (2H, m),1.69-1.89 (2H, m), 2.24-2.37 (1H, m), 2.43-2.55 (1H, m), 2.60-2.84 (2H,m), 3.70 (1H, d, J=13.9 Hz), 3.80 (1H, d, J=13.9 Hz), 4.14 (1H, brpeak), 4.25 (2H, q, J=7.1 Hz), 5.64 (1H, br peak), 6.68 (1H, d, J=15.5Hz), 6.88-6.93 (1H, m), 6.93-6.99 (1H, m), 7.20-7.30 (1H, m), 7.58 (1H,d, J=15.5 Hz), 7.92 (1H, s), 8.05 (1H, s);

MS (ES+) m/z 373.

Preparation 325

ethyl(2E)-3-(5-{[(3R)-1-(3-thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.40-1.82 (4H, m),2.17-2.32 (1H, m), 2.43-2.72 (3H, m), 3.51 (1H, d, J=13.4 Hz), 3.60 (1H,d, J=13.4 Hz), 4.10 (1H, brpeak), 4.25 (2H, q, J=7.1 Hz), 5.52 (1H, brpeak), 6.67 (1H, d, J=15.5 Hz), 7.06 (1H, d, J=4.9 Hz), 7.10 (1H, d,J=2.3 Hz), 7.29 (1H, dd, J=7.7, 3.0 Hz), 7.56 (1H, d, J=15.6 Hz), 7.9(1H, s), 8.05 (1H, s);

MS (ES+) m/z 373.

Preparation 326

ethyl(2E)-3-(5-{[(3R)-1-(2-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.53-1.91 (4H, m),2.26-2.45 (1H, m), 2.50-2.75 (3H, m), 3.63 (1H, d, J=13.8 Hz), 3.71 (1H,d, J=13.8 Hz), 4.05-4.18 (1H, m), 4.25 (2H, q, J=7.1 Hz), 5.68 (1H, brpeak), 6.65 (1H, d, J=15.5 Hz), 7.19 (1H, dd, J=7.5, 5.5 Hz), 7.38 (1H,d, J=7.7 Hz), 7.56 (1H, d, J=15.5 Hz), 7.66 (˜1H, t, J=7.5 Hz), 7.91(1H, s), 8.01 (1H, s), 8.55 (1H, d, J=4.4 Hz);

MS (ES+) m/z 368.

Preparation 327

ethyl(2E)-3-(5-{[(3R)-1-(3-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.50-1.84 (4H, m),2.20-2.35 (1H, m), 2.45-2.68 (3H, m), 3.50 (1H, d, J=14.7 Hz), 3.66 (1H,d, J=14.7 Hz), 4.14 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.45 (1H, brpeak), 6.66 (1H, d, J=15.5 Hz), 7.23-7.32 (1H, m), 7.56 (1H, d, J=15.5Hz), 7.66 (1H, d, J=7.8 Hz), 7.90 (1H, s), 8.04 (1H, s), 8.51 (1H, d,J=4.7 Hz), 8.54 (1H, s);

MS (ES+) m/z 368.

Preparation 328

ethyl(2E)-3-(5-{[(3R)-1-(cycloheptylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.04-1.23 (2H, m), 1.23-1.84 (18H, m),2.01-2.19 (3H, m), 2.33-2.48 (1H, m), 2.48-2.70 (2H, m), 4.10 (1H, brpeak), 4.25 (2H, q, J=7.0 Hz), 5.64 (1H, br peak), 6.66 (1H, d, J=15.8Hz), 7.57 (1H, d, J=15.4 Hz), 7.89 (1H, d, J=1.1 Hz), 8.05 (1H, d, J=1.5Hz);

MS (ES+) m/z 387.

Preparation 329

ethyl(2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.50-1.85 (4H, m),2.20-2.35 (1H, m), 2.46-2.86 (7H, m), 4.11 (1H, br peak), 4.25 (2H, q,J=7.1 Hz), 5.46 (1H, br peak), 6.67 (1H, d, J=15.5 Hz), 7.16-7.37 (5H,m), 7.56 (1H, d, J=15.5 Hz), 7.77 (1H, s), 8.04 (1H, s);

MS (ES+) m/z 381.

Preparation 330

ethyl(2E)-3-(5-{[(3R)-1-cycloheptyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.22-1.90 (19H, m), 2.35-2.72 (5H, m), 4.06(1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.68 (1H, br d, J=7.0 Hz), 6.66(1H, d, J=15.5 Hz), 7.58 (1H, d, J=15.5 Hz), 7.91 (1H, s), 8.05 (1H, s);

MS (ES+) m/z 373.

Preparation 331

ethyl(2E)-3-(5-{[(3R)-1-(4-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.50-1.86 (4H, m),2.24-2.36 (1H, m), 2.44-2.71 (3H, m), 3.48 (1H, d, J=14.8 Hz), 3.55 (1H,d, J=14.8 Hz), 4.06-4.20 (1H, m), 4.25 (2H, q, J=7.1 Hz), 5.42 (1H, brpeak), 6.68 (1H, d, J=15.5 Hz), 7.21-7.29 (2H, m), 7.57 (1H, d, J=15.5Hz), 7.92 (1H, s), 8.05 (1H, s), 8.55 (2H, d, J=5.8 Hz);

MS (ES+) m/z 368.

Preparation 332

ethyl(2E)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.96-1.36 (10H, m), 1.46-1.86 (7H, m),2.20-2.40 (1H, m), 2.40-2.65 (3H, m), 4.74 (1H, br d, J=11 Hz),3.81-3.98 (1H, m), 4.24 (2H, q, J=7.1 Hz), 5.36-5.55 (1H, m), 6.20 (1H,d, J=15.9 Hz), 6.40 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=15.8 Hz), 7.60(1H, dd, J=8.7, 2.3 Hz), 8.18 (1H, d, J=2.2 Hz);

MS (ES+) m/z 358.

Preparation 333

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cycloheptylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.98-1.15 (2H, m), 1.21-1.91 (24H, m),1.93-2.30 (4H, m), 2.50-2.76 (2H, m), 2.91 (1H, br peak), 4.28 (2H, q,J=7.2 Hz), 4.90 (1H, br peak), 6.46 (1H, d, J=16 Hz), 7.31 (1H, d, J=8Hz), 7.65 (1H, d, J=16 Hz), 7.80 (1H, dd, J=8, 2 Hz), 8.55 (1H, d, J=2Hz);

MS (ES+) m/z 472.

Preparation 334

ethyl(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.19-1.38 (4H, m), 1.57-1.86 (3H, m),2.28-2.43 (1H, m), 2.55-2.80 (3H, m), 2.80-2.98 (2H, m), 2.98-3.16 (2H,m), 3.16-3.35 (1H, m), 4.14 (1H, br peak), 4.26 (2H, q, J=7.3 Hz), 5.57(1H, br peak), 6.68 (1H, d, J=15.8 Hz), 7.10-7.22 (4H, m), 7.59 (1H, d,

MS (ES+) m/z 392.

Preparation 335

A mixture of ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (200 mg),(3R)-1-benzyl-3-pyrrolidinamine (0.244 mL), and N,N-dimethylformamide (5mL) was stirred for 3 hours at 60° C. The reaction mixture waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith saturated NaHCO₃ and brine, dried over MgSO₄, filtered, andevaporated in vacuo to give ethyl(2E)-3-(2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate(330 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.64-1.78 (1H, m),2.30-2.43 (2H, m), 2.61-2.75 (2H, m), 2.82-2.92 (1H, m), 3.59-3.70 (2H,m), 4.25 (2H, q, J=7 Hz), 4.50-4.62 (1H, m), 5.74 (1H, d, J=8 Hz), 6.28(1H, d, J=16 Hz), 7.22-7.34 (5H, m), 7.47 (1H, d, J=16 Hz), 8.43 (2H,s).

MS (ES+) m/z 353 (M+1).

Preparation 336

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(225 mg, 0.51 mmol) in EtOH (2.5 mL) was added 1N sodium hydroxidesolution (1.0 mL) at ambient temperature and the mixture was allowed tostand for 18 hrs. The reaction mixture was adjusted to PH 5.0 with 1mol/L hydrochloric acid and evaporated in vacuo to give(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid.

A mixture of(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (77 mg, 0.66 mmol), HOBt(89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) in DMF (4.5 mL) wasstirred at 0° C. for 1 hr and the mixture was stirred at ambienttemperature for 18 hrs. The reaction mixture was evaporated in vacuo andthe residue was partitioned between saturated sodium bicarbonatesolution and EtOAc. The organic layer was separated, evaporated invacuo. The residue was purified by preparative thin layer chromatography(chloroform-MeOH=10-1) to give tert-butyl[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate(181 mg, 69%) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.05-1.21 (2H, m), 1.46 (9H, s), 1.46-2.10(16H, m), 2.10-2.48 (2H, m), 2.48-2.85 (2H, m), 2.90-3.09 (1H, m),3.60-3.76 (1H, m), 3.90-4.05 (1H, m), 4.80-4.96 (1H, m), 4.96-5.11 (1H,m), 6.41 (1H, br peak), 7.30 (1H, d, J=8 Hz), 7.69 (1H, d, J=15 Hz),7.78 (1H, d, J=8 Hz), 8.56 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 336.

Preparation 337

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-methyl-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) 0.80-0.97 (2H, m), 1.11-1.34 (4H, m), 1.34-1.53(1H, m), 1.53-1.97 (10H, m), 2.11 (3H, d, J=1.3 Hz), 2.19-2.41 (4H, m),2.56 (1H, dd, J=9.4, 3.2 Hz), 2.69 (1H, dd, J=9.6, 6.3 Hz), 2.77-2.86(1H, m), 3.62-3.73 (1H, m), 3.95-4.07 (1H, m), 4.23-4.37 (1H, m),4.99-5.08 (2H, m), 6.38 (1H, d, J=8.7 Hz), 7.11 (1H, s), 7.47 (1H, dd,J=8.9, 2.4 Hz), 8.14 (1H, d, J=2.3 Hz), 8.58 (1H, br peak);

MS (ES+) m/z 443.

Preparation 338

(2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.30-1.71 (8H, m), 1.75-1.91 (2H, m),2.15-2.65 (3H, m), 3.40-3.55 (2H, m), 3.55-3.72 (1H, m), 3.85-4.05 (2H,m), 4.90-5.10 (2H, m), 6.36 (1H, d, J=8 Hz), 6.64 (1H, br peak),7.19-7.40 (5H, m), 7.53-7.68 (2H, m), 8.20 (1H, d, J=2 Hz);

MS (ES+) m/z 437.

Preparation 339

(2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.46-1.95 (10H, m), 2.19-2.36 (1H, m),2.36-2.66 (3H, m), 3.43 (1H, d, J=13.5 Hz), 3.50 (1H, d, J=13.5 Hz),3.56-3.70 (1H, m), 3.85-4.01 (2H, m), 5.00 (1H, br s), 5.32 (1H, brpeak), 6.24 (1H, br peak), 6.36 (1H, d, J=8.8 Hz), 7.20-8.34 (4H, m),7.57 (1H, d, J=9.3 Hz), 7.63 (1H, d, J=15.9 Hz), 8.21 (1H, s), 8.26 (1H,br peak);

MS (ES+) m/z 471.

Preparation 340

(2E)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.00-1.97 (18H, m), 2.23-2.84 (5H, m),3.56-3.80 (1H, m), 3.80-4.07 (2H, m), 5.00 (1H, br s), 5.88 (1H, brpeak), 6.27 (1H, br peak), 6.41 (1H, d, J=8.8 Hz), 7.50-7.72 (2H, m),8.14-8.42 (2H, m); MS (ES+) m/z 415.

Preparation 341

(2Z)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.77 (6H, m), 1.77-1.98 (3H, m),2.26-2.46 (2H, m), 2.60 (1H, dd, J=9.6, 3.0 Hz), 2.74 (1H, dd, J=9.6,6.3 Hz), 2.80-2.90 (1H, m), 3.60 (2H, s), 3.61-3.75 (1H, m), 3.91-4.07(1H, m), 4.35 (1H, br peak), 4.96-5.13 (2H, m), 6.36 (1H, d, J=8.8 Hz),6.82 (1H, d, J=40.4 Hz), 7.14-7.34 (4H, m), 7.72 (1H, dd, J=8.8, 2.1Hz), 8.25 (1H, d, J=1.8 Hz), 8.93 (1H, br peak).

Preparation 342

(2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.75 (2H, m), 1.75-1.95 (6H, m),1.95-2.11 (1H, m), 3.58-3.83 (4H, m), 3.83-4.13 (4H, m), 4.13-4.25 (1H,m), 5.00 (1H, br s), 5.12 (1H, br d, J=7.3 Hz), 6.51 (1H, t, J=4.7 Hz),6.70 (1H, br peak), 7.65 (1H, d, J=15.2 Hz), 7.90 (1H, s), 8.05 (1H, s),8.30 (2H, d, J=4.7 Hz), 8.35 (1H, br peak);

MS (ES+) m/z 426.

Preparation 343

(2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.96 (9H, m), 2.12-2.34 (1H, m),2.44-2.70 (3H, m), 3.45 (1H, d, J=13.3 Hz), 3.51 (1H, d, J=13.3 Hz),3.90-4.04 (1H, m), 4.04-4.16 (1H, m), 5.00 (1H, br s), 5.48 (1H, brpeak), 6.68 (1H, br peak), 7.03 (2H, t, J=8.6 Hz), 7.22-7.35 (2H, m),7.64 (1H, d, J=15.2 Hz), 7.88 (1H, s), 8.04 (1H, s), 8.32 (1H, br peak);

MS (ES+) m/z 456.

Preparation 344

(2E)-3-(5-{[(3R)-1-(2-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.54-1.96 (10H, m), 2.29-2.49 (1H, m),2.54-2.78 (3H, m), 3.60-3.76 (3H, m), 3.90-4.03 (1H, m), 4.06-4.19 (1H,m), 5.01 (1H, br s), 5.72 (1H, br peak), 7.68 (1H, br peak), 7.19 (1H,dd, J=7.0, 4.9 Hz), 7.38 (1H, d, J=7.7 Hz), 7.56-7.73 (2H, m), 7.90 (1H,s), 8.00 (1H, s), 8.36 (1H, br peak), 8.56 (1H, d, J=4.7 Hz);

MS (ES+) m/z 439.

Preparation 345

(2E)-3-(5-{[(3R)-1-(3-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.96 (10H, m), 2.20-2.40 (1H, m),2.40-2.70 (3H, m), 3.55 (2H, s), 3.60-3.73 (1H, m), 3.90-4.05 (1H, m),4.05-4.20 (1H, m), 5.02 (1H, br s), 5.36-5.51 (1H, m), 6.68 (1H, brpeak), 7.23-7.36 (1H, m), 7.58-7.74 (2H, m), 7.90 (1H, s), 8.04 (1H, s),8.39 (1H, br peak), 8.50-8.63 (2H, m);

MS (ES+) m/z 439.

Preparation 346

(2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.98 (8H, m), 2.30-2.48 (2H, m),2.61-2.88 (6H, m), 2.96-3.11 (1H, m), 3.57-3.72 (1H, m), 3.90-4.04 (1H,m), 4.41-4.55 (1H, m), 5.01 (1H, br s), 5.30 (1H, d, J=7.7 Hz), 6.70(1H, br peak), 7.15-7.35 (5H, m), 7.64 (1H, d, J=15.0 Hz), 7.85 (1H, s),8.05 (1H, s);

MS (ES+) m/z 438.

Preparation 347

(2E)-3-(5-{[(3R)-1-(cycloheptylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.04-1.23 (2H, m), 1.30-1.96 (20H, m),1.96-2.20 (3H, m), 2.33-2.48 (1H, m), 2.48-2.69 (2H, m), 3.58-3.72 (1H,m), 3.89-4.03 (1H, m), 4.03-4.15 (1H, m), 5.01 (1H, br s), 5.61 (1H, brpeak), 6.71 (1H, br peak), 7.64 (1H, d, J=15 Hz), 7.86 (1H, s), 8.03(1H, s), 8.28 (1H, br peak);

MS (ES+) m/z 458.

Preparation 348

(2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.35-1.96 (16H, m), 2.17-2.35 (1H, m),2.43-2.88 (7H, m), 3.60-3.72 (1H, m), 3.90-4.04 (1H, m), 4.11 (1H, br.peak), 5.01 (1H, br s), 5.38-5.55 (1H, m), 6.70 (1H, br peak), 7.15-7.38(5H, m), 7.51 (1H, d, J=15 Hz), 7.75 (1H, s), 8.01 (1H, s), 8.34 (1H, brpeak);

MS (ES+) m/z 452.

Preparation 349

(2E)-3-(5-{[(3R)-1-cycloheptyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.30-1.96 (21H, m), 2.35-2.46 (1H, m),2.46-2.70 (4H, m), 3.59-3.70 (1H, m), 3.86-4.01 (1H, m), 4.05 (1H, brpeak), 5.02 (1H, br s), 5.61-5.74 (1H, m), 6.65 (1H, br peak), 7.63 (1H,d, J=15 Hz), 7.88 (1H, s), 8.02 (1H, s), 8.34 (1H, br peak);

MS (ES+) m/z 444.

Preparation 350

tert-butyl[(3R)-1-(1-adamantylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.18-2.40 (36H, m), 2.64 (1H, br peak), 2.87(1H, br peak), 3.63-3.76 (1H, m), 3.91-4.10 (1H, m), 4.86 (1H, br peak),4.95-5.10 (1H, m), 6.41 (1H, br peak), 7.30 (1H, d, J=9 Hz), 7.59-7.90(2H, m), 8.59 (1H, s);

MS (ES+) m/z 581.

Preparation 351

(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.08-1.35 (6H, m), 1.45-1.99 (10H, m),1.99-2.12 (1H, m), 2.25-2.41 (1H, m), 2.41-2.54 (1H, m), 2.71 (1H, dd,J=9.3, 2.5 Hz), 2.82 (1H, dd, J=9.8, 6.7 Hz), 2.89-3.01 (1H, m),3.61-3.75 (1H, m), 3.94-4.06 (1H, m), 4.27-4.43 (1H, m), 4.99-5.06 (1H,m), 5.06-5.21 (1H, m), 6.37 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=40.4 Hz),7.72 (1H, dd, J=8.8, 2.1 Hz), 8.26 (1H, s);

MS (ES+) m/z 433.

Preparation 352

(2E)-3-(6-{[(3R)-1-(4-methylbenzyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.40-1.95 (10H, m), 2.10-2.35 (4H, m),2.35-2.66 (3H, m), 3.43 (1H, d, J=12.9 Hz), 3.50 (1H, d, J=12.9 Hz),3.60-3.71 (1H, m), 3.86-4.03 (2H, m), 4.99 (1H, br peak), 5.40 (1H, brpeak), 6.25 (1H, br peak), 6.36 (1H, d, J=8.7 Hz), 7.13 (1H, d, J=7.9Hz), 7.20 (1H, d, J=7.9 Hz), 7.52-7.69 (2H, m), 8.14-8.35 (2H, m);

MS (ES+) m/z 451.

Preparation 353

(2E)-N-(tetrahydro-2H-pyran-2-yloxy)-3-(5-{[(3R)-1-(2-thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.96 (9H, m), 2.21-2.39 (1H, m),2.39-2.55 (1H, m), 2.55-2.85 (2H, m), 3.59-3.70 (1H, m), 3.70 (1H, d,J=13.9 Hz), 3.80 (1H, d, J=13.9 Hz), 3.90-4.04 (1H, m), 4.06-4.20 (1H,m), 5.00 (1H, br s), 5.64 (1H, br peak), 6.68 (1H, br peak), 6.85-6.91(1H, m), 6.95 (1H, dd, J=4.8, 3.5 Hz), 7.21-7.30 (1H, m), 7.63 (1H, d,J=15.1 Hz), 7.90 (1H, s), 8.02 (1H, s), 8.34 (1H, br peak);

MS (ES+) m/z 444.

Preparation 354

(2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.78 (4H, m), 1.78-1.95 (3H, m),2.28-2.48 (2H, m), 2.60-2.72 (2H, m), 2.82-2.95 (1H, m), 3.60 (2H, s),3.61-3.71 (1H, m), 3.90-4.04 (1H, m), 4.46 (1H, br peak), 5.01 (1H, brs), 5.21 (1H, d, J=7 Hz), 6.67 (1H, br peak), 7.00 (1H, dd, J=8.7, 8.7Hz), 7.27 (1H, dd, J=8.4, 5.6 Hz), 7.61 (1H, d, J=15.1 Hz), 7.85 (1H,s), 8.03 (1H, s), 8.34 (1H, br peak);

MS (ES+) m/z 442.

Preparation 355

(2E)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 0.96-1.35 (7H, m), 1.35-1.95 (13H, m),2.20-2.40 (1H, m), 2.40-2.67 (3H, m), 2.67-2.83 (1H, m), 3.60-3.72 (1H,m), 3.80-4.06 (2H, m), 4.99 (1H, br s), 5.30-5.51 (1H, m), 6.26 (1H, brpeak), 6.39 (1H, d, J=8.7 Hz), 7.57 (1H, d, J=8.2 Hz), 7.62 (1H, d,J=15.0 Hz), 8.13-8.35 (1H, m);

MS (ES+) m/z 429.

Preparation 356

tert-butyl [(3R)1-(cycloheptylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ 0.95-1.18 (2H, m), 1.18-1.93 (28H, m),1.93-2.09 (1H, m), 2.09-2.38 (2H, m), 2.38-2.75 (2H, m), 2.75-2.95 (1H,m), 3.61-3.75 (1H, m), 3.89-4.06 (1H, m), 4.82-4.96 (1H, m), 4.96-5.09(1H, m), 6.20-6.50 (1H, m), 7.29 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=16.5Hz), 7.78 (1H, dd, J=8.3, 2.6 Hz), 8.57 (1H, s);

MS (ES+) m/z 543.

Preparation 357

(2E)-3-(5-{[(3R)-1-(4-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.45-1.97 (10H, m), 2.20-2.36 (1H, m),2.44-2.71 (3H, m), 3.52 (2H, s), 3.60-3.71 (1H, m), 3.88-4.04 (1H, m),4.15 (1H, br peak), 5.02 (1H, br s), 5.43 (1H, br peak), 6.65 (1H, brpeak), 7.20-7.31 (2H, m), 7.63 (1H, d, J=15.0 Hz), 7.90 (1H, s), 8.03(1H, s), 8.39 (1H, br peak), 8.56 (2H, d, J=5.8 Hz);

MS (ES+) m/z 439.

Preparation 358

(2E)-N-(tetrahydro-2H-pyran-2-yloxy)-3-(5-{[(3R)-1-(3-thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.48-1.95 (10H, m), 2.18-2.34 (1H, m),2.45-2.74 (3H, m), 3.51 (1H, d, J=13.5 Hz), 3.59 (1H, d, J=13.5 Hz),3.61-3.71 (1H, m), 3.90-4.05 (1H, m), 4.05-4.15 (1H, m), 5.01 (1H, brs), 5.53 (1H, br peak), 6.66 (1H, br peak), 7.05 (1H, d, J=5.0 Hz), 7.10(1H, d, J=2.3 Hz), 7.23-7.32 (1H, m), 7.62 (1H, d, J=15.0 Hz), 7.88 (1H,s), 8.02 (1H, s), 8.31 (1H, br peak);

MS (ES+) m/z 444.

Preparation 359

(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.96 (10H, m), 2.25-2.45 (1H, m),2.54-2.80 (3H, m), 2.80-2.98 (2H, m), 2.98-3.15 (2H, m), 3.20-3.35 (1H,m), 3.59-3.71 (1H, m), 3.90-4.04 (1H, m), 4.09-4.20 (1H, m), 5.02 (1H,br s), 5.59 (1H, br peak), 6.68 (1H, br peak), 7.10-7.30 (5H, m), 7.65(1H, d, J=15.4 Hz), 7.91 (1H, s), 8.05 (1H, s), 8.34 (1H, br peak);

MS (ES+) m/z 464.

Preparation 360

(2Z)-2-fluoro-3-(6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.52-1.98 (9H, m), 2.25-2.49 (5H, m), 2.60(1H, dd, J=9.7, 3.1 Hz), 2.75 (1H, dd, J=9.7, 6.4 Hz), 2.78-2.90 (1H,m), 3.57 (1H, d, J=12.9 Hz), 3.64 (1H, d, J=12.9 Hz), 3.64-3.74 (1H, m),3.93-4.08 (1H, m), 4.26-4.42 (1H, m), 5.00-5.07 (1H, m), 5.11 (1H, d,J=7.7 Hz), 6.35 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=40.5% Hz), 7.13 (2H,d, J=7.9 Hz), 7.21 (2H, d, J=7.9 Hz), 7.71 (1H, dd, J=8.8, 2.2 Hz), 8.25(1H, d, J=1.9 Hz); MS (ES+) m/z 455, 909.

Preparation 361

To a suspension of lithium aluminum hydride (70 mg, 1.8 mmol) intetrahydrofuran (2 mL) was added a solution of ethyl6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinate (250 mg, 0.74 mmol) intetrahydrofuran (5 mL) dropwise at 0° C. under nitrogen and the mixturewas stirred at same temperature for 3 hrs. To the reaction mixture wasadded methanol and water dropwise at 0′ and the mixture was stirred for1 h. The precipitate was removed by vacuum filtration and the filtratewas evaporated in vacuo. The residue was partitioned between water andethyl acetate. The organic layer was separated, washed with brine, driedover magnesium sulfate, and evaporated in vacuo to give(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)methanol (219 mg,100%) as an oil.

MS (ES+) m/z 298.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 362

(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)methanol

¹H-NMR (300 MHz, CDCl₃) δ 0.75-0.95 (2H, m), 1.06-1.31 (3H, m),1.38-1.85 (10H, m), 2.00-2.14 (2H, m), 2.14-2.30 (1H, m), 2.30-2.59 (3H,m), 3.80-3.93 (1H, m), 4.52 (2H, s), 5.11 (1H, br peak), 6.40 (1H, d,J=8.6 Hz), 7.46 (1H, dd, J=8.5, 2.3 Hz), 8.04 (1H, d, J=2.3 Hz).

Preparation 363

To a solution of 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinaldehyde(110 mg, 0.37 mmol) in tetrahydrofuran (4 mL) was added(carbethoxymethylene)triphenylphosphorane (260 mg, 0.75 mmol) and themixture was stirred at ambient temperature for 18 hrs. The reactionmixture was evaporated in vacuo and the residue was partitioned betweenwater and EtOAc. The organic layer was separated, washed water andbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by preparative thin layer chromatography(chloroform-MeOH=15-1) to give ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)acrylate (77mg, 57%) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.19-1.40 (3H, m), 1.49-1.82 (4H, m),2.19-2.36 (1H, m), 2.36-2.68 (3H, m), 3.40-3.5.9 (2H, m), 4.06-4.40 (3H,m), 5.40 (1H, br peak), 6.19 (1H, d, J=15.8 Hz), 6.38 (1H, d, J=8.1 Hz),7.19-7.40 (5H, m), 7.40-7.75 (2H, m), 8.16 (1H, s);

MS (ES+) m/z 366.

The following compounds were obtained in a similar manner to that ofPreparation 363.

Preparation 364

ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-methylacrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.80-0.97 (2H, m), 1.11-1.28 (4H, m), 1.34(3H, t, J=7.1 Hz), 1.37-1.52 (1H, m), 1.60-1.85 (5H, m), 2.13 (3H, d,J=1.4 Hz), 2.19-2.41 (4H, m), 2.57 (1H, dd, J=10, 3 Hz), 2.69 (1H, dd,J=10, 6 Hz), 2.81 (1H, dt, J=8, 4 Hz), 4.20-4.38 (3H, m), 5.04 (1H, d,J=7.7 Hz), 6.39 (1H, d, J=8.7 Hz), 7.53 (1H, s), 7.56 (1H, dd, J=8.7,2.3 Hz), 8.21 (1H, d, J=2.3 Hz);

MS (ES+) m/z 372.

Preparation 365

ethyl(2E)-3-(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.78-0.96 (2H, m), 1.06-1.40 (5H, m),1.40-1.84 (11H, m), 2.00-2.25 (3H, m), 2.38-2.64 (3H, m), 3.96 (1H, brpeak), 4.25 (2H, q, J=7.1 Hz), 5.49 (1H, br peak), 6.21 (1H, d, J=15.9Hz), 6.39 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=15.9 Hz), 7.61 (1H, dd,J=8.7, 2.4 Hz), 8.19 (1H, d, J=2.2 Hz).

Preparation 366

To a solution of tert-butyl(3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate(3.3 g) in EtOH (19.3 ml) was added solution of 4N HCl in dioxane (19.3ml) at ambient temperature and the mixture was stirred at sametemperature for 1.5 hr. Diisopropylether was added to the mixture andprecipitate was collected by filtration to give ethyl(2Z)-3-{5-chloro-6-[(3R)-3-piperidinylamino]-3-pyridinyl)-2-fluoroacrylatedihydrochloride (2.98 g).

¹H-NMR(DMSO-d₆): δ 1.29(3H, t, J=7.2 Hz), 1.61-1.97(4H, m),2.70-2.81(1H, m), 2.88-2.99(1H, m), 3.13-3.22(1H, m), 3.23-3.31(1H, m),4.28(2H, q, J=7.2 Hz), 4.42-4.51(1H, m), 7.03(1H, d, J=37.6 Hz),7.96(1H, d, J=1.9 Hz), 8.37(1H, d, J=1.9 Hz),

(+)ESI-MS: 328(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 366.

Preparation 367

ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylatedihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7.1 Hz), 1.54-1.68 (1H, m),1.68-1.86 (1H, m), 1.86-2.11 (2H, m), 2.84-3.02 (2H, m), 3.10-3.23 (1H,m), 3.23-3.44 (1H, m), 4.10-4.30 (3H, m), 6.55 (1H, d, J=16.0 Hz), 7.00(1H, d, J=8.9 Hz), 7.63 (1H, d, J=16.1 Hz), 8.21 (1H, d, J=8.9 Hz), 8.31(1H, d, J=1.7 Hz), 8.80-9.15 (2H, m), 9.26-9.43 (1H, m).

Preparation 368

ethyl (2Z)-2-fluoro-3-{6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 1.29 (3H, t, J=7.1 Hz), 1.93-2.09 (1H, m),2.20-2.40 (1H, m), 3.12-3.60 (4H, m), 4.28 (2H, q, J=7.1 Hz), 4.60 (1H,br peak), 6.99 (1H, d, J=9.2 Hz), 7.10 (1H, d, J=37.3 Hz), 8.05 (1H, d,J=9.2 Hz), 8.34 (1H, s), 9.10 (1H, br peak), 9.45 (2H, br peak);

MS (ES+) m/z 280.

Preparation 369

ethyl (2Z)-2-fluoro-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylatedihydrochloride

¹H-NMR(DMSO-d₆): δ 1.30(3H, t, J=7.0 Hz), 1.59-1.69(1H, m),1.74-1.84(1H, m), 1.89-1.99(1H, m), 2.00-2.08(1H, m), 2.89-3.04(2H, m),3.11-3.20(1H, m), 3.34-3.44(1H, m), 4.24-4.36(3H, m), 7.16(1H, d, J=36.8Hz), 7.18(1H, d, J=9.2 Hz), 8.14(1H, d, J=9.2 Hz), 8.34(1H, s),9.13-9.73(3H, m),

(+)ESI-MS: 294(M+H)+.

Preparation 370

To a solution of ethyl6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 18.1mmol) in ethanol (200 mL) were added ammonium formate (6.83 g, 108 mmol)and 10% Pd/C (20% w/w, 1.2 g) at ambient temperature and the mixture washeated to reflux with stirring for 8 hrs. After cooling, the catalyst inthe reaction mixture was removed by filtration. The solvent wasevaporated in vacuo. The residue was purified by silica gel columnchromatography (NH, CHCl₃ only-CHCl₃:MeOH/50:1˜25:1) to give ethyl6-[(3R)-3-piperidinylamino]nicotinate (4.5 g, 100%) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7.1 Hz), 1.40-1.67 (3H, m),1.67-1.83 (1H, m), 1.83-1.99 (1H, m), 2.65 (1H, dd, J=11.6, 7.0 Hz),2.70-2.81 (1H, m), 2.81-2.93 (1H, m), 3.16 (1H, dd, J=11.4, 3.3 Hz),3.77-3.92 (1H, m), 4.33 (2H, q, J=7.1 Hz), 5.29 (1H, br d, J=7.1 Hz),6.37 (1H, d, J=8.9 Hz), 7.97 (1H, dd, J=8.8, 2.3 Hz), 8.74 (1H, d, J=2.3Hz);

MS (ES+) m/z 250.

The following compound was obtained in a similar manner to that ofPreparation 370.

Preparation 371

ethyl 6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 0.77-0.97 (2H, m), 1.05-1.30 (3H, m), 1.36(3H, t, J=7.1 Hz), 1.40-1.86 (10H, m), 1.97-2.25 (3H, m), 2.37-2.64 (3H,m), 3.84-4.08 (1H, m), 4.30 (2H, q, J=7.1 Hz), 5.59 (1H, br peak), 6.35(1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.6, 2.0 Hz), 8.74 (1H, d, J=2.0 Hz).

Preparation 372

1) To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (1.00 g),2,3-dimethylbenzaldehyde (720 mg), N,N-diisopropylethylamine (1.87 mL),and ethanol (10 mL) was added sodium triacetoxyborohydride (2.28 g).After stirring for 3 hours at room temperature, the reaction mixture waspartitioned between ethyl acetate and saturated NH₄Cl. The organic layerwas washed with H₂O, dried over MgSO₄, filtered, and evaporated invacuo.

2) To a mixture of above product and ethyl acetate (10 mL) was added 4Nhydrogen chloride in ethyl acetate (8.40 mL) at 4° C. After stirring atroom temperature for 5 hours, the reaction mixture was neutrized withsaturated NaHCO₃. The resulting mixture was evaporated in vacuo. Theresidue was added chloroform, dried over Na₂SO₄, filtered, andevaporated in vacuo to give(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinamine (193 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.41-1.53 (1H, m), 2.12-2.46 (3H, m), 2.27(3H, s), 2.29 (3H, s), 2.64-2.77 (2H, m), 3.42-3.51 (1H, m), 3.58 (2H,s), 7.00-7.14 (3H, m),

MS (ES+) m/z 205 (M+1).

Preparation 373

To a suspension of sodium hydride (60%, 208 mg, 5.2 mmol) intetrahydrofuran (2 mL) was added a solution of ethyl(diethoxyphosphoryl)(fluoro)acetate (1.26 g, 5.2 mmol) intetrahydrofuran (5 mL) dropwise at 0° C. and the mixture was stirred atsame temperature for 1 hr. To the mixture was added a solution of6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}nicotinaldehyde (1.0g, 3.5 mmol) in tetrahydrofuran (10 mL) dropwise at 0° C. and themixture was stirred at same temperature for 4 hrs. The reaction mixturewas evaporated in vacuo and the residue was partitioned between waterand EtOAc. The organic layer was separated, washed water and brine,dried over magnesium sulfate, and evaporated in vacuo to a mixture ofethyl(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylateand ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(1:1) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 0.80-1.00 (2H, m), 1.10-1.51 (9H, m),1.51-1.85 (4H, m), 2.15-2.40 (4H, m), 2.51-2.61 (1H, m), 2.61-2.72 (1H,m), 2.72-2.86 (1H, m), 4.20-4.40 (3H, m), 5.11 (1H, br d, J=8.4 Hz),6.39 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=36.3 Hz), 8.03 (1H, dd, J=9.2,2.6 Hz), 8.25 (1H, d, J=2.6 Hz).

Preparation 374

To a solution of ethyl 6-[(3R)-3-piperidinylamino]nicotinate (3.9 g,15.6 mmol) in ethanol (40 mL) was added di-tert-butyl dicarbonate (3.76g, 17.2 mmol) at ambient temperature and the mixture was stirred at sametemperature for 18 hrs. The reaction mixture was evaporated in vacuo andthe residue was partitioned between water and EtOAc. The organic layerwas separated, washed water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (hexane:EtOAc/1:1) to give ethyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}nicotinate (5.4 g,99%) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7.1 Hz), 1.44 (9H, s),1.51-1.82 (2H, m), 1.90-2.06 (1H, m), 3.09-3.36 (2H, m), 3.48-3.60 (1H,m), 3.70-3.91 (2H, m), 4.33 (2H, q, J=7.1 Hz), 4.39-5.03 (1H, m), 6.40(1H, d, J=8.8 Hz), 8.01 (1H, dd, J=8.7, 2.3 Hz), 8.75 (1H, d, J=2.2 Hz);

MS (ES+) m/z 350.

Preparation 375

To a solution of ethyl(2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride(300 mg, 0.86 mmol) in DMF (4 mL) were added triethylamine (349 mg, 3.45mmol) and 4-chlorobenzoyl chloride (181 mg, 1.03 mmol) at 0° C. undernitrogen and the mixture was stirred at same temperature for 1 hr and atambient temperature for 2 hrs. The reaction mixture was poured intowater and extracted with EtOAc. The organic layer was separated, washedwater and brine, dried over magnesium sulfate, and evaporated in vacuo.The residue was purified by preparative thin layer chromatography(hexane-EtOAc=1-1) to give ethyl(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate(270 mg, 76%) as an amorphous powder.

¹H-NMR (300 MHz, DMSO-d₆) δ 1.24 (3H, t, J=7.1 Hz), 1.41-1.76 (2H, m),1.76-2.07 (2H, m), 2.78-3.49 (3H, m), 3.49-4.46 (4H, m), 6.33 (1H, d,J=15.9 Hz), 6.44-6.60 (1H, m), 7.08-7.28 (1H, m), 7.28-7.59 (5H, m),7.70-7.87 (1H, m), 8.00-8.32 (1H, m);

MS (ES+) m/z 414.

Preparation 376

The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.8 g) and1-[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]thiourea (1.09 g) in CH₃CN(16 mL) was stirred at 70° C. for 2 hrs. To the reaction mixture wasadded an AcOEt (32 mL) and isolated precipitate was collected byfiltration to give ethyl(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}thiazol-4-yl)acrylatehydrochloride (1.10 g).

¹H-NMR(DMSO-d₆): δ 0.80-1.36(6H, m), 1.24(3H, t, J=7.1 Hz),1.52-2.56(8H, m), 2.92-4.06(5H, m), 4.16(2H, q, J=7.1 Hz), 4.31-4.61(1H,m), 6.38 and 6.40(total 1H, each d, J=each 15.3 Hz), 7.24(1H, s),7.36(1H, d, J=15.3 Hz), 8.26-8.45(1H, m), 10.51(1H, s)

(+)ESI-MS: 364(M+H)+.

Preparation 377

A mixture of 5-bromo-2-pyrazinecarboxylic acid (650 mg) in thionylchloride (2.35 ml) was stirred under reflux condition.

After 3 hrs, the reaction mixture was evaporated.

To this residue in tetrahydrofuran (10 ml) was added sodium borohydride(465 mg) under ice cooling.

The mixture was quenched with water and extracted with ethyl acetate(three times).

The combined organic layer was washed with water, dried over Na₂SO₄,filtered and evaporated to give 230 mg (39%) of(5-bromo-2-pyridinyl)methanol as an oil.

MASS (ESI+,): 210.1, 211.0 (M+Na).

¹H-NMR (400 MHz, CDCl₃): δ 4.73 (2H, s), 7.20 (1H, d, J=8.2 Hz), 7.82(1H, dd, J=8.2 and 1.8 Hz), 8.63 (1H, d, J=1.8 Hz).

Preparation 378

A mixture of (5-bromo-2-pyridinyl)methanol (200 mg), ethyl(triphenylphosphoranylidene)acetate (408 mg) and manganese oxide (370mg) in dioxane (5 ml) was stirred at 60° C. for 5 hrs.

After cooling, the reaction mixture was filtered.

Filtrate was evaporated.

The residue was column chromatographed on silica gel to give 150 mg(55%) of ethyl (2E)-3-(5-bromo-2-pyridinyl}acrylate as a solid.

MASS (ESI+): m/z 258.1(M+1), 259.0 (M+2).

¹HNMR (400 MHz, CDCl₃): δ 1.34 (3H, t, J=7.1 Hz), 4.28 (2H, q, J=7.1Hz), 6.91 (1H, d, J=15.5 Hz), 7.31 (1H, d, J=8.3 Hz), 7.62 (1H, d,J=15.5 Hz), 7.84 (1H, dd, J=8.3 and 2.2 Hz), 8.69 (1H, d, J=2.2 Hz).

Preparation 379

To a solution of ethyl 5,6-dichloronicotinate (10.0 g) andN,N-diisopropylethylamine (17.4 mL) in 1,3-dimethyl-2-imidazolidinone(100 mL) was added tert-butyl (3R)-3-amino-1-piperidinecarboxylate(10.9) at ambient temperature and the mixture was stirred at 100° C. for9 hr. The reaction mixture was poured into a mixture of AcOEt and water.The separated organic layer was added ice-water and the mixture wasadjusted to pH 3.5 with 1N-HCl. The separated organic layer was washedwith water, dried over magnesium sulfate and evaporated in vacuo to giveethyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate(16.74 g).

¹H-NMR(DMSO-d₆): δ 1.26-1.51(10H, m), 1.30(3H, t, J=7.1 Hz),1.60-1.71(2H, m), 1.83-1.95(1H, m), 2.78-3.25(2H, m), 3.56-4.12(3H, m),4.27(2H, q, J=7.1 Hz), 6.82(1H, s), 7.96(1H, d, J=1.9 Hz), 8.56(1H, d,J=1.9 Hz),

(+)ESI-MS: 384(M+H)+, 406(M+Na)+.

Preparation 380

0.94 M solution of diisobutylaluminium hydride in hexane (139 ml) wasadded to dropwise a solution of ethyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate(16.7 g) in THF (250 ml) with stirred at −5 to 0° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at 0° C. for1.5 hr. To the reaction mixture was added MeOH (26.4 ml) was stirred at0 to 10 for 20 minutes. The potassium sodium tartarate tetrahydrate(36.8 g) was added to a above solution and the resultant mixture wasstirred at ambient temperature for 3 hours. The reaction mixture wasfiltrated and the filtrate was evaporated in vacuo. The residue waschromatographed on silicagel eluting with solution of CHCl₃ and AcOEt(3:2). The eluted fractions containing the desired product werecollected and evaporated in vacuo to give tert-butyl tert-butyl(3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate(10.29 g).

(+)ESI-MS: 342(M+H)+, 364(M+Na)+

¹H-NMR(DMSO-d₆): δ 1.24-1.48(10H, m), 1.59-1.71(2H, m), 1.82-1.92(1H,m), 2.75-3.14(2H, m), 3.53-3.96(3H, m), 4.33(2H, d, J=5.6 Hz), 5.08(1H,t, J=5.6 Hz), 5.82(1H, s), 7.56(1H, d, J=2.0 Hz), 7.93(1H, d, J=2.0 Hz).

The following compound was obtained in a similar manner to that ofPreparation 380.

Preparation 381

tert-butyl(3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate

¹H-NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.50-1.66 (3H, m), 1.66-1.81(1H, m), 1.89-2.07 (1H, m), 2.90-3.30 (2H, m), 3.52-3.66 (1H, m),3.66-3.78 (1H, m), 3.78-4.03 (1H, m), 4.44-4.61 (3H, m), 6.44 (1H, d,J=9.1 Hz), 7.49 (1H, dd, J=8.5, 2.4 Hz), 8.06 (1H, d, J=2.1 Hz);

MS (ES+) m/z 308.

Preparation 382

A mixture of tert-butyl(3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate(10.0 g) and MnO₂ (25.4 g) in CHCl₃ (200 ml) was stirred at 60° C. for3.5 hours. After removal of the insoluble material, and the solvent wasevaporated in vacuo to give tert-butyl(3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate(9.08 g).

¹H-NMR(DMSO-d₆): δ 1.24-1.52 (10H, m), 1.63-1.81(2H, m), 1.85-1.95(1H,m), 2.79-3.21(2H, m), 3.59-4.00(2H, m), 4.04-4.16(1H, m), 7.08(1H, s),7.96(1H, d, J=1.9 Hz), 8.56(1H, d, J=1.9 Hz), 9.76(1H, s),

(+)ESI-MS: 340(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 382.

Preparation 383

6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 1.44-2.38 (5H, m), 2.38-2.71 (3H, m),3.41-3.60 (2H, m), 4.00-4.40 (1H, m), 6.41 (1H, d, J=8.8 Hz), 7.13-7.41(5H, m), 7.86 (1H, d, J=8.8 Hz), 8.46 (1H, s), 9.74 (1H, s);

MS (ES+) m/z 296.

Preparation 384

6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 0.76-0.95 (2H, m), 1.06-1.331 (3H, m),1.39-1.85 (10H, m), 2.00-2.20 (3H, m), 2.31-2.49 (1H, m), 2.49-2.70 (2H,m), 3.92-4.20 (1H, m), 5.88 (1H, br peak), 6.42 (1H, d, J=8.8 Hz), 7.88(1H, dd, J=8.5, 1.7 Hz), 8.50 (1H, d, J=2.2 Hz), 9.75 (1H, s);

MS (ES+) m/z 302.

Preparation 385

6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 0.77-0.97 (2H, m), 1.07-1.32 (3H, m),1.40-1.84 (10H, m), 2.00-2.23 (3H, m), 2.34-2.68 (3H, m), 4.02 (1H, brpeak), 5.87 (1H, br peak), 6.42 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=8.8Hz), 8.49 (1H, d, J=1.9 Hz), 9.75 (1H, s);

MS (ES+) m/z 302.

Preparation 386

The mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (2.51 mL),MgBr₂ (2.73 g), Et₃N (1.89 mL) in THF (45 mL) was stirred at 3-5° C. for1 hr and to the mixture was dropwise added a solution of tert-butyl(3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate(3.0 g) in THF (21 mL) at 3-5° C. The reaction mixture was stirred atsame temperature for 2.5 hrs. The reaction mixture was poured into amixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5with 1N-HCl. The separated organic layer was washed with water, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel using a mixture of AcOEt andhexane (1:2 v/v) as an eluant. The eluted fractions containing thedesired product were collected and evaporated in vacuo to givetert-butyl(3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate(3.38 g).

¹H-NMR(DMSO-d₆): δ 1.25-1.48(10H, m), 1.29(3H, t, J=7.1 Hz),1.64-1.75(2H, m), 1.84-1.93(1H, m), 2.77-3.20(2H, m), 3.57-4.07(3H, m),4.27(2H, q, J=7.1 Hz), 6.60(1H, s), 7.01(1H, d, J=37.5 Hz), 7.94(1H, d,J=1.8 Hz), 8.36(1H, d, J=1.8 Hz),

(+)ESI-MS: 428(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 386.

Preparation 387

(3R)-3-({5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

¹H-NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7.1 Hz), 1.47 (9H, s), 1.93(1H, br peak), 2.16-2.33 (1H, m), 3.15-3.39 (1H, m), 3.39-3.59 (2H, m),3.74 (1H, dd, J=11.3, 6.0 Hz), 4.35 (2H, q, J=7.1 Hz), 4.43 (1H, brpeak), 7.77-4.90 (1H, m), 6.43 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=36.1Hz), 7.83 (1H, dd, J=8.8, 2.1 Hz), 8.26 (1H, s);

MS (ES+) m/z 380.

Preparation 388

tert-butyl(3R)-3-({5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate

(+)ESI-MS: 394(M+H)+

Preparation 389

To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (416 mg) inDMF (10 mL) was added (3R)-1-cyclohexyl-3-pyrrolidinaminedihydrochloride (849 mg) and K₂CO₃ (1.35 g). After stirring for 2 hoursat 120° C., the reaction mixture was partitioned between ethyl acetateand H₂O. The organic layer was washed with H₂O, dried over MgSO₄,filtered, and evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give ethyl(2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(318 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.11-1.34 (6H, m), 1.32 (3H, t, J=7 Hz),1.57-2.09 (6H, m), 2.30-2.44 (2H, m), 2.67-2.74 (1H, m), 2.78-2.84 (1H,m), 2.98-3.06 (1H, m), 4.25 (2H, q, J=7 Hz), 4.39-4.50 (1H, m), 5.32(1H, d, J=8 Hz), 6.68 (1H, d, J=16 Hz), 7.57 (1H, d, J=16 Hz), 7.88 (1H,d, J=1 Hz), 8.06 (1H, d, J=1 Hz).

MS (ES+) m/z 345 (M+1).

Preparation 390

The mixture of ethyl(2E)-3-(5-{([(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate(235 mg, 0.59 mmol) and 1N-NaOH (1.2 mL) in EtOH (2 mL) was stirred atambient temperature for 1 hr and the mixture was allowed to stand for 18hrs. The reaction mixture was adjusted to PH 5.0 with 1 mol/Lhydrochloric acid and evaporated in vacuo to give(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid (218 mg, 100%).

¹H-NMR (300. MHz, DMSO-d₆) δ 1.21-1.40 (1H, m), 1.40-1.60 (1H, m),1.60-1.77 (1H, m), 1.77-1.90 (1H, m), 1.90-2.15 (2H, m), 2.53-2.90 (2H,m), 3.35-3.60 (2H, m), 3.90-4.03 (1H, m), 6.45 (1H, d, J=15.5 Hz),7.24-7.40 (4H, m), 7.46 (1H, d, J=7.9 Hz), 7.98 (1H, s), 8.10 (1H, s);

MS (ES+) m/z 373, 375.

The following compounds were obtained in a similar manner to that ofPreparation 390.

Preparation 391

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) 0.74-1.01 (2H, m), 1.01-1.34 (3H, m),1.34-2.10 (10H, m), 2.59-3.65 (6H, m), 4.04-4.45 (1H, m), 6.26 (1H, d,J=16.9 Hz), 6.55 (1H, d, J=8.7 Hz), 7.28 (1H, br peak), 7.47 (1H, d,J=15.8 Hz), 7.81 (1H, d, J=8.1 Hz), 8.21 (1H, s);

MS (ES+) m/z 344.

Preparation 392

(2E)-3-(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 0.78-1.05 (2H, m), 1.05-1.34 (3H, m),1.34-2.11 (10H, m), 2.53-3.66 (6H, m), 3.94-4.41 (1H, m), 6.28 (1H, d,J=16.1 Hz), 6.55 (1H, d, J=8.8 Hz), 7.31 (1H, br peak), 7.48 (1H, d,J=15.4 Hz), 7.83 (1H, d, J=9.5 Hz), 8.24 (1H, s), 9.25 (1H, br peak).

Preparation 393

(2Z)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 0.81-1.03 (2H, m), 1.03-1.31 (3H, m), 1.39(9H, s), 1.53-1.82 (6H, m), 1.90-2.08 (1H, m), 2.19-2.40 (1H, m),2.79-3.00 (2H, m), 3.00-3.81 (4H, m), 5.10 (1H, br peak), 6.87 (1H, d,J=34.1 Hz), 7.41 (1H, d, J=8.4 Hz), 8.09 (1H, dd, J=8.1, 1.8 Hz), 8.15(1H, s).

Preparation 394

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 0.83-2.04 (13H, m), 2.22-2.64 (2H, m),2.94-3.20 (2H, m), 3.51-4.41 (3H, m), 6.24 (1H, d, J=15.9 Hz), 6.45-6.64(1H, m), 7.03-7.28 (1H, m), 7.41-7.54 (1H, m), 7.74-7.85 (1H, m), 8.20(1H, br s);

MS (ES+) m/z 358.

Preparation 395

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 1.24-1.41 (1H, m), 1.45-1.65 (1H, m),1.65-1.80 (1H, m), 1.80-1.95 (1H, m), 1.95-2.25 (2H, m), 2.56-2.76 (1H,m), 2.83-2.98 (1H, m), 3.59 (2H, s), 3.90-4.05 (1H, m), 6.45 (1H, d,J=15.5 Hz), 7.22-7.45 (3H, m), 7.50-7.60 (1H, m), 8.00 (1H, s), 8.11(1H, s);

MS (ES+) m/z 373, 375.

Preparation 396

(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d₆) δ 1.43-2.09 (2H, m), 2.65-3.21 (1H, m),3.54-3.95 (2H, m), 4.03-4.20 (1H, m), 4.39-4.44 (2H, m), 6.24 (1H, d,J=15.9 Hz), 6.45-6.60 (1H, m), 7.07-7.21 (1H, m), 7.29-7.60 (5H, m),7.67-7.84 (1H, m), 7.94-8.27 (1H, m);

MS (ES+) m/z 386.

Preparation 397

A mixture of(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylicacid (218 mg, 0.59 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (82mg, 0.70 mmol), HOBt (103 mg, 0.76 mmol) and EDCI (146 mg, 0.76 mmol) inDMF (6 mL) was stirred at 0° C. for 1 hr and the mixture was stirred atambient temperature for 18 hrs. The reaction mixture was evaporated invacuo and the residue was partitioned between saturated sodiumbicarbonate solution and EtOAc. The organic layer was separated, washedwater and brine, dried over magnesium sulfate, and evaporated in vacuo.The residue was purified by silica gel column chromatography(chloroform-MeOH=95-5) to give(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(251 mg, 91%) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.99 (10H, m), 2.19-2.36 (1H, m),2.44-2.70 (3H, m), 3.45 (1H, d, J=13.4 Hz), 3.53 (1H, d, J=13.4 Hz),3.58-3.74 (1H, m), 3.90-4.04 (1H, m), 4.04-4.20 (1H, m), 5.01 (1H, brs), 5.49 (1H, br peak), 6.70 (1H, br peak), 7.15-7.36 (4H, m), 7.64 (1H,d, J=15.2 Hz), 7.90 (1H, s), 8.03 (1H, s), 8.36 (1H, br peak);

MS (ES+) m/z 472.

The following compounds were obtained in a similar manner to that ofPreparation 397.

Preparation 398

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 0.76-0.96 (3H, m), 1.08-1.32 (3H, m),1.39-1.94 (15H, m), 1.98-2.25 (3H, m), 2.35-2.61 (3H, m), 3.59-3.62 (1H,m), 3.86-4.03 (2H, m), 5.00 (1H, br s), 5.46 (1H, br peak), 6.25 (1H, brpeak), 6.37 (1H, d, J=8.7 Hz), 7.53-7.70 (2H, m), 8.22 (1H, d, J=2.0Hz), 8.25 (1H, br peak);

MS (ES+) m/z 443.

Preparation 399

(2E)-3-(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 0.76-0.96 (3H, m), 1.08-1.32 (3H, m),1.39-1.94 (15H, m), 1.98-2.25 (3H, m), 2.35-2.61 (3H, m), 3.59-3.62 (1H,m), 3.86-4.03 (2H, m), 5.00 (1H, br s), 5.46 (1H, br peak), 6.25 (1H, brpeak), 6.37 (1H, d, J=8.7 Hz), 7.53-7.70 (2H, m), 8.22 (1H, d, J=2.0Hz), 8.25 (1H, br peak);

MS (ES+) m/z 443.

Preparation 400

tert-butyl[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl](5-{(1Z)-2-fluoro-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ 0.66-0.93 (2H, m), 1.04-1.46 (18H, m),1.48-2.06 (8H, m), 2.06-2.29 (3H, m), 2.36-2.71 (3H, m), 2.81-2.96 (1H,m), 3.60-3.75 (1H, m), 3.93-4.06 (1H, m), 4.78-4.95 (1H, m), 5.06 (1H,s), 6.96 (1H, d, J=39.2 Hz), 7.31 (1H, d, J=8.5 Hz), 7.92 (1H, dd,J=8.4, 2.3 Hz), 8.61 (1H, d, J=2.2 Hz);

MS (ES+) m/z 547.

Preparation 401

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) 1.48-1.95 (10H, m), 2.20-2.35 (1H, m), 2.54-2.80(3H, m), 3.50-3.72 (3H, m), 3.89-4.04 (1H, m), 4.06-4.20 (1H, m), 5.00(1H, br s), 5.71 (1H, br peak), 6.66 (1H, br peak), 7.16-7.28 (2H, m),7.30-7.43 (2H, m), 7.62 (1H, d, J=15.1 Hz), 7.86 (1H, s), 8.00 (1H, s),8.35 (1H, br peak);

MS (ES+) m/z 472.

Preparation 402

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d₆) δ 0.93-1.97 (18H, m), 1.97-2.15 (1H, m),2.32-2.59 (1H, m), 2.98-3.42 (2H, m), 3.53-3.81 (2H, m), 3.81-4.28 (4H,m), 4.50-4.95 (1H, m), 5.00 (1H, br s), 6.10-6.76 (2H, m), 7.54-7.75(2H, m), 8.10-8.40 (2H, m);

MS (ES+) m/z 457.

Preparation 403

(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.35-1.96 (8H, m), 1.96-2.17 (1H, m),3.08-3.71 (4H, m), 3.71-4.06 (4H, m), 4.04-4.75 (1H, m), 5.00 (1H, brs), 6.10-6.63 (2H, m), 7.14-7.46 (4H, m), 7.46-7.70 (2H, m), 7.94-8.43(2H, m);

MS (ES+) m/z 485.

Preparation 404

To a solution of ethyl(2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl)acrylate dihydrochloride(300 mg, 0.86 mmol) in DMF (6 mL) were added diiopropylethylamine (366mg, 2.84 mmol) and 6-chloropyrimidine (128 mg, 1.11 mmol) at ambienttemperature and the mixture was stirred at ambient temperature for 18hrs. The reaction mixture was evaporated in vacuo and the residue waspartitioned between water and EtOAc. The organic layer was separated,washed water and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by silica gel column chromatography(chloroform-MeOH=95-5/hexane-EtOAc=1/4) to give ethyl(2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate(141 mg, 46%) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.61-1.75 (1H, m),1.75-1.91 (2H, m), 1.96-2.12 (1H, m), 3.66-3.84 (2H, m), 3.84-3.98 (1H,m), 4.00-4.14 (1H, m), 4.20 (1H, dd, J=13.6, 3.2 Hz), 4.25 (2H, q, J=7.1Hz), 5.13 (1H, br d, J=7.4 Hz), 6.52 (1H, t, J=4.7 Hz), 6.69 (1H, d,J=15.6 Hz), 7.58 (1H, d, J=15.6 Hz), 7.94 (1H, s), 8.09 (1H, s), 8.32(2H, d, J=4.7 Hz);

MS (ES+) m/z 355.

Preparation 405

The mixture of ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(0.73 g) and 1N-NaOH (3.44 mL) in MeOH (20 mL) was stirred at 60° C. for3 hr. To the reaction mixture was added 1N-NaCl 3.44 mL and the mixturewas evaporated in vacuo to give(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (0.68 g).

¹H-NMR(DMSO-d₆): δ 0.83-0.96(2H, m), 1.08-1.28(3H, m), 1.56-1.86(10H,m), 2.42-2.75(4H, m), 2.75-3.10(2H, m), 4.33-4.45(1H, m), 6.73(1H, s),7.77(1H, d, J=37.5 Hz), 7.88(1H, d, J=1.7 Hz), 8.26(1H, d, J=1.7 Hz),(−)ESI-MS: 394(M−H)−.

The following compounds were obtained in a similar manner to that ofPreparation 405.

Preparation 406

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylicacid (−)ESI-MS: 334(M−H)−.

Preparation 407

(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylicacid (−)ESI-MS: 388(M−H)−.

Preparation 408

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (−)ESI-MS: 366(M−H)−.

Preparation 409

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR(DMSO-d₆): δ 1.00-1.15(1H, m), 1.16-1.31(2H, m), 1.31-1.45(2H, m),1.50-2.07(9H, m), 2.66-3.29(5H, m), 4.40-4.56(1H, m), 6.54-6.73(1H, m),6.66(1H, d, J=37.6 Hz), 7.86(1H, d, J=1.7 Hz), 8.22(1H, d, J=1.7 Hz),(−)ESI-MS: 380(M−H)−.

Preparation 410

(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR(DMSO-d₆): δ 1.29-1.43(1H, m), 1.64-1.93(3H, m), 2.25-2.54(2H, m),2.85-2.98(1H, m), 3.07-3.18(1H, m), 3.91(2H, s), 4.12-4.24(1H, m),6.58(1H, d, J=8.9 Hz), 6.78(1H, d, J=38.1 Hz), 7.21-7.41(4H, m),7.44-7.52(2H, m), 7.71(1H, dd, J=2.2 Hz, 8.9 Hz), 8.20(1H, d, J=2.2 Hz),(−)ESI-MS: 354(M−H)−.

Preparation 411

(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (−)ESI-MS: 360(M−H)−.

Preparation 412

(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (−)ESI-MS: 346(M−H)−.

Preparation 413

(2Z)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (−)ESI-MS: 332(M−H)−.

Preparation 414

EDCI (0.32 g) was added to the solution of(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (0.68 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.24 g), andHOBT (0.28 g) in DMF (13.6 ml) and the mixture was stirred at ambienttemperature for 20 hr. The reaction mixture was poured into a mixture ofAcOEt and aq NaHCO₃. The separated organic layer was washed with water,dried over magnesium sulfate and evaporated in vacuo. The residue wascrystallization with solution of iPE and hexane to give(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(0.57 g).

¹H-NMR(DMSO-d₆): δ 0.77-0.92(2H, m), 1.06-1.27(3H, m), 1.40-1.81(16H,m), 2.08(2H, d, J=7.1 Hz), 2.16-2.44(3H, m), 2.48-2.61(1H, m),3.47-3.56(1H, m), 4.01-4.11(1H, m), 4.12-4.22(1H, m), 4.97(1H, s),6.43(1H, d, J=8.2 Hz), 6.79(1H, d, J=39.7 Hz), 7.87(1H, s, J=1.8 Hz),8.29(1H, d, J=1.8 Hz), 11.76(1H, s),

(+)ESI-MS: 495(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 414.

Preparation 415

(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆):d 1.45-1.76(10H, m), 2.12-2.28(2H, m), 2.44-2.55(1H, m),2.62-2.73(1H, m), 3.42-3.58(3H, m), 4.01-4.11(1H, m), 4.14-4.25(1H, m),4.97(1H, s), 6.47(1H, d, J=8.2 Hz), 6.77(1H, d, J=39.8 Hz),7.21-7.27(1H, m), 7.29-7.34(4H, m), 7.86(1H, d, J=1.9 Hz), 8.27(1H, d,J=1.9 Hz), 11.76(1H, s),

(+)ESI-MS: 489(M+H)+.

Preparation 416

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆): δ 0.74-0.91(2H, m), 1.07-1.27(3H, m), 1.32-1.83(13H,m), 2.11-2.79(7H, m), 3.48-3.56(1H, m), 3.88-3.98(1H, m), 4.10-4.21(1H,m), 4.89(1H, s), 6.44(1H, d, J=15.2 Hz), 6.97(1H, s), 7.17(1H, d, J=15.2Hz), 7.86(1H, d, J=6.6 Hz), 11.19(1H, s),

(+)ESI-MS: 435(M+H)+.

Preparation 417

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

(+)ESI-MS: 467(M+H)+.

Preparation 418

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆): δ 0.98-1.10(1H, m), 1.11-1.29(4H, m), 1.39-1.78(15H,m), 2.24-2.34(1H, m), 2.36-2.46(2H, m), 2.49-2.60(1H, m), 2.68-2.76(1H,m), 3.47-3.55(1H, m), 4.00-4.18(2H, m), 4.97(1H, s), 6.43(1H, d, J=8.2Hz), 6.78(1H, d, J=39.7 Hz), 7.87(1H, d, J=1.9 Hz), 8.29(1H, d, J=1.9Hz), 11.76(1H, s),

(+)ESI-MS: 481(M+H)+.

Preparation 419

(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆): δ 1.17-1.30(1H, m), 1.44-1.75(8H, m), 1.77-2.04(3H, m),2.57-2.67(1H, m), 2.82-2.92(1H, m), 3.43-3.54(3H, m), 3.90-4.12(2H, m),4.96(1H, s), 6.52(1H, d, J=8.8 Hz), 6.69(1H, d, J=40.4 Hz), 6.95(1H, d,J=8.0 Hz), 7.20-7.27(1H, m), 7.28-7.34(4H, m), 7.65 and 7.67(total 1H,each d, J=each 2.2 Hz), 8.19(1H, d, J=2.2 Hz), 11.66(1H, s),

(+)ESI-MS: 455(M+H)+.

Preparation 420

(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆): δ 0.73-0.88(2H, m), 1.05-1.29(4H, m), 1.37-1.94(17H,m), 2.05(2H, d, J=7.2 Hz), 2.57-2.67(1H, m), 2.79-2.88(1H, m),3.47-3.54(1H, m), 3.93(1H, s), 4.02-4.11(1H, m), 4.96(1H, s), 6.53(1H,d, J=8.9 Hz), 6.70(1H, d, J=38.9 Hz), 6.89(1H, d, J=7.8 Hz), 6.67(1H,dd, J=2.2 Hz, 8.9 Hz), 8.21(1H, d, J=2.2 Hz), 11.66(1H, s),

(+)ESI-MS: 461(M+H)+.

Preparation 421

(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆): δ 0.96-1.29(6H, m), 1.39-1.85(14H, m), 2.01-2.11(1H,m), 2.16-2.32(2H, m), 2.61-2.71(1H, m), 2.86-2.96(1H, m), 3.47-3.55(1H,m), 3.87(1H, s), 4.02-4.11(1H, m), 4.96(1H, s), 6.53(1H, d, J=8.9 Hz),6.70(1H, d, J=40.0 Hz), 6.90(1H, d, J=7.8 Hz), 7.67(1H, dd, J=2.2 Hz,8.9 Hz), 8.21(1H, d, J=2.2 Hz), 11.66(1H,

(+)ESI-MS: 447(M+H)+.

Preparation 422

(2Z)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR(DMSO-d₆): δ 1.14-2.06(19H, m), 2.44-2.56(2H, m), 2.64-2.75(1H,m), 2.88-2.98(1H, m), 3.46-3.54(1H, m), 3.84-3.97(1H, m), 4.00-4.11(1H,m), 4.94-4.98(1H, m), 6.54(1H, d, J=9.0 Hz), 6.70(1H, d, J=40.0 Hz),6.94(1H, d, J=7.9 Hz), 7.67(1H, dd, J=2.2 Hz, 9.0 Hz), 8.21(1H, d, J=2.2Hz), 11.66(1H, s),

(+)ESI-MS: 433(M+H)+.

Preparation 423

A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41mmol), (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (565mg, 2.11 mmol) and triethylamine (928 mg, 9.17 mmol) was stirred at 100°C. for 6 hrs. The reaction mixture was evaporated in vacuo and theresidue was partitioned between water and EtOAc. The organic layer wasseparated, washed water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (35% EtOAc/hexane-50% EtOAc/hexane) to give ethyl(2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(245 mg, 47%) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.1 Hz), 1.65-1.80 (1H, m),2.30-2.46 (2H, m), 2.60-2.73 (2H, m), 2.82-2.95 (1H, m), 3.60 (2H, s),4.25 (2H, q, J=7.1 Hz), 4.46 (1H, br peak), 5.20 (1H, d, J=7.7 Hz), 6.68(1H, d, J=15.5 Hz), 7.01 (1H, dd, J=8.6, 8.6 Hz), 7.28 (1H, dd, J=8.4,5.6 Hz), 7.56 (1H, d, J=15.5 Hz), 7.88 (1H, s), 8.05 (1H, s);

MS (ES+) m/z 371.

The following compound was obtained in a similar manner to that ofPreparation 423.

Preparation 424

ethyl(2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.56-1.79 (1H, m),2.30-2.47 (2H, m), 2.61-2.87 (6H, m), 2.96-3.09 (1H, m), 4.26 (2H, q,J=7.1 Hz), 4.41-4.55 (1H, m), 5.25 (1H, d, J=7.8 Hz), 6.68 (1H, d,J=15.5 Hz), 7.16-7.35 (5H, m), 7.58 (1H, d, J=15.5 Hz), 7.87 (1H, s),8.06 (1H, s);

MS (ES+) m/z 367.

Preparation 425

To a mixture of 2-chloro-5-iodopyrimidine (7.62 g), palladium(II)acetate (356 mg), tri(o-tolyl)phosphine (965 mg), and DMF (32 mL) wasadded ethyl acrylate (17.2 mL) and N,N-diisopropylethylamine (13.8 mL).After stirring for 3 hours at 100° C., the reaction mixture waspartitioned between ethyl acetate and H₂O. The organic layer was driedover MgSO₄, filtered, and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel to give ethyl(2E)-3-(2-chloro-5-pyrimidinyl)acrylate (2.32 g).

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz),6.58 (1H, d, J=16 Hz), 7.58 (1H, d, J=16 Hz), 8.76 (2H, s).

Preparation 426

Sodium triacetoxyborohydride (0.56 g) was added a mixture of ethyl(2Z)-3-{5-chloro-6-[(3R)-3-piperidinylamino]-3-pyridinyl}-2-fluoroacrylatedihydrochloride (0.7 g), Et₃N (0.49 mL) and cyclohexanecarboxaldehyde(0.23 mL) in CH₂Cl₂ (14 mL) and the mixture was stirred at ambienttemperature for 20 hr. The reaction mixture was poured into a mixture ofCHCl₃ and aq NaHCO₃. The separated organic layer was washed with water,dried over magnesium sulfate and evaporated in vacuo to give ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(0.74 g).

¹H-NMR(DMSO-d₆): δ 0.77-0.89(2H, m), 1.09-1.24(3H, m), 1.29(3H, t, J=7.1Hz), 1.41-1.54(2H, m), 1.55-1.79(8H, m), 2.08(2H, d, J=7.1 Hz),2.20-2.40(3H, m), 2.90-2.59(1H, m), 4.14-4.22(1H, m), 4.27(2H, q, J=7.1Hz), 6.51(1H, d, J=8.2 Hz), 6.99(1H, d, J=37.6 Hz), 7.92(1H, d, J=1.9Hz), 8.34(1H, d, J=1.9 Hz),

(+)ESI-MS: 424(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 426.

Preparation 427

ethyl(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): δ 1.29(3H, t, J=7.1 Hz), 1.46-1.73(4H, m),2.15-2.27(2H, m), 2.46-2.55(1H, m), 2.62-2.73(1H, m), 3.43-3.58(2H, m),4.15-4.30(1H, m), 4.27(2H, q, J=7.1 Hz), 6.57(1H, d, J=8.2 Hz), 6.98(1H,d, J=37.5 Hz), 7.20-7.27(1H, m), 7.29-7.34(4H, m), 7.91(1H, d, J=1.9Hz), 8.32(1H, d, J=1.9 Hz),

(+)ESI-MS: 418(M+H)+.

Preparation 428

ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): δ 1.25-1.37(2H, m), 1.29(3H, t, J=7.1 Hz),1.41-1.80(10H, m), 2.13-2.25(2H, m), 2.49-2.62(2H, m), 2.72-2.80(1H, m),4.12-4.21(1H, m), 4.27(2H, q, J=7.1 Hz), 6.55(1H, d, J=8.2 Hz), 6.99(1H,d, J=37.6 Hz), 7.91(1H, d, J=1.9 Hz), 8.34(1H, d, J=1.9 Hz),

(+)ESI-MS: 396(M+H)+.

Preparation 429

ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): δ 0.98-1.10(1H, m), 1.00-1.26(4H, m), 1.29(3H, t, J=7.1Hz), 1.40-1.51(1H, m), 1.51-1.79(8H, m), 2.24-2.33(1H, m), 2.35-2.46(2H,m), 2.49-2.59(1H, m), 2.68-2.75(1H, m), 4.09-4.19(1H, m), 4.27(2H, q,J=7.1 Hz), 6.52(1H, d, J=8.1 Hz), 6.99(1H, d, J=37.6 Hz), 7.91(1H, d,J=1.9 Hz), 8.33(1H, d, J=1.9 Hz),

(+)ESI-MS: 410(M+H)+.

Preparation 430

ethyl(2Z)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): δ 1.18-1.40(3H, m), 1.28(3H, t, J=7.1 Hz),1.40-1.94(10H, m), 1.94-2.05(1H, m), 2.45-2.56(1H, m), 2.64-2.75(1H, m),2.87-2.99(1H, m), 3.87-3.99(1H, m), 4.26(2H, q, J=7.1 Hz), 6.56(1H, d,J=8.9 Hz), 6.91(1H, d, J=38.2 Hz), 7.06(1H, d, J=8.0 Hz), 7.73(1H, dd,J=2.0 Hz, 8.9 Hz), 8.27(1H, d, J=2.0 Hz),

(+)ESI-MS: 362(M+H)+.

Preparation 431

ethyl(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): δ 0.98-1.33(5H, m), 1.28(3H, t, J=7.1 Hz),1.39-1.84(9H, m), 2.03-2.11(1H, m), 2.17-2.30(2H, m), 2.62-2.69(1H, m),2.87-2.93(1H, m), 3.89(1H, s), 4.26(2H, q, J=7.1 Hz), 6.55(1H, d, J=9.0Hz), 6.91(1H, d, J=38.2 Hz), 7.01(1H, d, J=7.8 Hz), 7.72(1H, dd, J=2.3Hz, 9.0 Hz), 8.26(1H, d, J=2.3 Hz),

(+)ESI-MS: 376(M+H)+.

Preparation 432

ethyl(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): 0.74-0.87(2H, m), 1.08-1.31(4H, m), 1.28(3H, t, J=7.0Hz), 1.37-1.94(11H, m), 2.03-2.07(2H, m), 2.57-2.65(1H, m),2.79-2.86(1H, m), 3.89-3.99(1H, m), 4.26(2H, q, J=7.0 Hz), 6.54(1H, d,J=8.9 Hz), 6.91(1H, d, J=38.2 Hz), 7.02(1H, d, J=7.8 Hz), 7.73(1H, dd,J=2.3 Hz, 8.9 Hz), 8.26(1H, d, J=2.3 Hz),

(+)ESI-MS: 390(M+H)+.

Preparation 433

ethyl(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR(DMSO-d₆): 1.21-1.31(1H, m), 1.28(3H, t, J=7.1 Hz), 1.47-1.56(1H,m), 1.64-1.72(1H, m), 1.80-1.94(2H, m), 1.94-2.03(1H, m), 2.57-2.66(1H,m), 2.83-2.90(1H, m), 3.48(2H, dd, J=13.4 Hz, 17.6 Hz), 3.93-4.05(1H,m), 4.25(2H, q, J=7.1 Hz), 6.54(1H, d, J=8.9 Hz), 6.91(1H, d, J=38.2Hz), 7.08(1H, d, J=8.0 Hz), 7.20-7.27(1H, m), 7.28-7.34(4H, m), 7.72(1H,dd, J=2.2 Hz, 8.9 Hz), 8.25(1H, d, J=2.2 Hz),

(+)ESI-MS: 384(M+H)+.

Preparation 434

A mixture of cyclohexanecarboxylic acid (133 mg, 1.03 mmol), ethyl(2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride(300 mg, 0.86 mmol), HOBt (163 mg, 1.21 mmol) and EDCI (174 mg, 1.12mmol) in DMF (6 mL) was stirred at 0° C. for 1 hr and the mixture wasstirred at ambient temperature for 18 hrs. The reaction mixture wasevaporated in vacuo and the residue was partitioned between saturatedsodium bicarbonate solution and EtOAc. The organic layer was separated,washed water and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by preparative thin layer chromatography(hexane-EtOAc=1-1) to give ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate(313 mg, 94%) as an amorphous powder.

¹H-NMR (300 MHz, CDCl₃) δ 0.95-2.14 (17H, m), 2.34-2.61 (1H, m),3.05-3.43 (2H, m), 3.43-4.31 (4H, m), 4.56-4.94 (1H, m), 6.16-6.29 (1H,m), 6.36-6.54 (1H, m), 7.51-7.66 (2H, m), 8.15-8.25 (1H, m);

MS (ES+) m/z 386.

Preparation 435

To a solution of ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl}acrylate(360 mg) in methanol (10 ml) was added 1NNaOH (5 ml) at room temperatureand stirred for 2 hrs.

After then, the reaction mixture was neutralized with 1N HCl (5 ml).

The mixture was evaporated under reduced pressure and co-evaporated withtoluene (twice).

To the residue in DMF (10 ml) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (180 mg), HOBt (138 mg) andWSCD (318 mg) and the mixture was stirred overnight.

After 12 hours, water was added and extracted with ethyl acetate (Threetimes).

Combined organic layer was washed with water, dried over Na₂SO₄,filtered and evaporated.

The reside was column chromatographed on silica gel (CHCl₃ MeOH) to givecrude product.

Crude product was purified by HPLC (Yamazene packed column, 26 mm×100mm) to give 190 mg (44%) of(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamideas an oil.

MASS (ESI+): m/z=423.3(M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.50-2.20 (7H, m), 2.30-3.00 (5H, m), 3.69(2H, s), 3.90-4.10 (2H, m), 4.48 (1H, br.s), 5.01 (1H, br.s), 6.77 (1H,dd, J=8.4 and 2.8 Hz), 7.18 (1H, d, J=8.4 Hz), 7.25-7.40 (6H, m), 7.61(1H, d, J=15.2 Hz), 7.98 (1H, s).

Preparation 436

A mixture of ethyl(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylateand ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(1:1, 1.15 g), di-tert-butyl dicarbonate (1.34 g, 6.1 mmol) and4-dimethylaminopyridine (11 mg) in tetrahydrofuran (20 mL) was stirredat 60° C. for 48 hrs. The reaction mixture was evaporated in vacuo andthe residue was partitioned between water and EtOAc. The organic layerwas separated, washed water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (CHCl₃/methanol=95/5) and preparative thin layerchromatography (CHCl₃/methanol=15/1) to give ethyl(2Z)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(575 mg) as an oil.

¹H-NMR (300 MHz, CDCl₃) δ 0.70-0.90 (2H, m), 1.04-1.30 (3H, m),1.30-1.49 (12H, m), 1.49-1.78 (7H, m), 1.89-2.10 (1H, m), 2.10-2.30 (3H,m), 2.40-2.74 (3H, m), 2.84-2.99 (1H, m), 4.36 (2H, q, J=7.1 Hz), 4.89(1H, br peak), 6.90 (1H, d, J=35.0 Hz), 7.32 (1H, d, J=9.0 Hz), 8.0 (1H,d, J=9.0 Hz), 8.60 (1H, d, J=2.2 Hz);

MS (ES+) m/z 476.

Preparation 437

Ethyl (2E)-3-(5-chloro-2-Pyrazinyl)acrylate (250 mg, 1.18 mmol) and(5R)-5-amino-1-(benzyloxy)-2-piperidinone (388 mg, 1.86 mmol) werecombined in 1,4-dioxane (4 mL) at ambient temperature. To this solutionwere added palladium(II) acetate (18 mg, 0.8 mmol) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (46 mg, 0.1 mmol)at the same temperature and the mixture was stirred for 5 minutes. Tothe resulting mixture was added cesium carbonate (536 mg, 1.86 mmol) andthe mixture was heated at 95° C. for 24 hrs. The reaction mixture wasevaporated in vacuo and the residue was partitioned between water andEtOAc. The organic layer was separated, washed water and brine, driedover magnesium sulfate, and evaporated in vacuo. The residue waspurified by silica gel column chromatography (CHCl₃/methanol=95/1) togive ethyl(2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)acrylate(202 mg, 43%) as an amorphous solid.

¹H-NMR (300 MHz, CDCl₃) δ 1.54-1.75 (3H, m), 1.75-1.94 (3H, m),1.94-2.07 (2H, m), 2.50-2.60 (2H, m), 3.20 (1H, dd, J=11.7, 5.1 Hz),3.61-3.79 (2H, m), 3.90-4.05 (1H, m), 4.23-4.36 (1H, m), 4.61 (1H, br d,J=6.6 Hz), 4.98 (1H, d, J=11.0 Hz), 5.03 (1H, br peak), 5.08 (1H, d,J=11.0 Hz), 6.70 (1H, br peak), 7.31-7.41 (3H, m), 7.41-7.50 (2H, m),7.64 (1H, d, J=15.8 Hz), 7.80 (1H, s), 8.00 (1H, s), 8.36 (1H, br peak);

MS (ES+) m/z 468, 935.

Preparation 438

To a solution of tert-butyl(3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate(3.65 g, 11.9 mmol) in dioxane (50 mL) was added manganese(IV) oxide(7.7 g, 89 mmol) and, (carbethoxymethylene)triphenylphosphorane (6.2 g,17.8 mmol). After stirring for 18 hrs at 60, a resulting precipitate wasfiltered and the filtrate was evaporated in vacuo and the residue waspartitioned between water and EtOAc. The organic layer was separated,washed water and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by silica gel column chromatography(CHCl₃/methanol=95/5) to give tert-butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate(3.99 g, 89%).

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.43 (9H, s),1.50-1.82 (2H, m), 1.90-2.06 (1H, m), 3.09-3.36 (2H, m), 3.48-3.62 (1H,m), 3.71-3.90 (2H, m), 4.25 (2H, q, J=7.1 Hz), 4.76-4.90 (1H, m), 6.23(1H, d, J=15.9 Hz), 6.43 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=16.0 Hz),7.64 (1H, dd, J=8.8, 2.3 Hz), 8.21 (1H, d, J=2.2 Hz);

MS (ES+) m/z 376.

Preparation 439

To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (500 mg) inDMF (5 mL) was added (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (951 mg)and Et₃N (1.15 mL). After stirring for 3 hours at 120° C., the reactionmixture was partitioned between ethyl acetate and H₂O. The organic layerwas washed with H₂O, dried over MgSO₄, filtered, and evaporated invacuo. The residue was purified by column chromatography on silica gelto give ethyl(2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(601 mg).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.21-1.28 (3H, m), 1.84-2.29 (2H, m),3.25-3.85 (4H, m), 4.10-4.21 (2H, m), 4.33-4.53 (1H, m), 6.47-6.58 (1H,m), 7.46-7.61 (6H, m), 7.96-8.31 (3H, m).

MS (ES+) m/z 401 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 439.

Preparation 440

ethyl(2E)-3-(5-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.58-1.75 (1H, m), 2.28(3H, s), 2.30 (3H, s), 2.33-2.43 (2H, m), 2.62-2.73 (2H, m), 2.86-2.94(1H, m), 3.58-3.68 (2H, m), 4.25 (2H, q, J=7 Hz), 4.39-4.50 (1H, m),5.20 (1H, d, J=7 Hz), 6.67 (1H, d, J=16 Hz), 7.01-7.12 (3H, m), 7.57(1H, d, J=16 Hz), 7.87 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz).

MS (ES+) m/z 381 (M+1).

Preparation 441

ethyl(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.67-1.76 (1H, m),2.33-2.51 (2H, m), 2.69-2.82 (2H, m), 2.63-3.01 (1H, m), 3.78 (2H, s),4.25 (2H, q, J=7 Hz), 4.42-4.53 (1H, m), 5.25 (1H, d, J=8 Hz), 6.68 (1H,d, J=16 Hz), 7.16-7.28 (2H, m), 7.34-7.45 (2H, m), 7.57 (1H, d, J=16Hz), 7.88 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz).

MS (ES+) m/z 385 (M−1).

Preparation 442

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.80 (6H, t, J=7 Hz), 1.16-1.66 (5H, m), 1.35(3H, t, J=7 Hz), 1.44 (9H, s), 1.94-2.09 (1H, m), 2.14-2.28 (3H, m),2.50-2.70 (3H, m), 2.80-2.89 (1H, m), 4.28 (2H, q, J=7 Hz), 4.83-4.94(1H, m), 6.46 (1H, d, J=16 Hz), 7.26-7.34 (1H, m), 7.66 (1H, d, J=16Hz), 7.81 (1H, dd, J=2, 8 Hz), 8.56 (1H, d, J=2 Hz).

MS (ES+) m/z 446 (M+1).

Preparation 443

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-isobutyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.84 (6H, d, J=7 Hz), 1.35 (3H, t, J=7 Hz),1.45 (9H, s), 1.58-1.72 (1H, m), 1.94-2.06 (1H, m), 2.10-2.27 (3H, m),2.47-2.68 (3H, m), 2.86-2.94 (1H, m), 4.28 (2H, q, J=7 Hz), 4.86-4.94(1H, m), 6.46 (1H, d, J=16 Hz), 7.32 (1H, d, J=8 Hz), 7.66 (1H, d, J=16Hz), 7.81 (1H, dd, J=2, 8 Hz), 8.55 (1H, d, J=2 Hz).

MS (ES+) m/z 418 (M+1).

Preparation 444

ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-6-methyl-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.60-1.77 (1H, m),2.22-2.97 (8H, m), 3.64-3.67 (2H, m), 4.24 (2H, q, J=7 Hz), 4.56-4.66(1H, m), 5.00-5.06 (1H, m), 6.71 (1H, d, J=16 Hz), 7.25-7.35 (5H, m),7.56 (1H, d, J=16 Hz), 7.95 (1H, s).

MS (ES+) m/z 367 (M+1).

Preparation 445

ethyl(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.64-1.77 (1H, m),2.32-2.47 (2H, m), 2.63-2.75 (2H, m), 2.85-2.93 (1H, m), 3.61 (2H, s),4.25 (2H, q, J=7 Hz), 4.43-4.52 (1H, m), 5.20 (1H, d, J=8 Hz), 6.68 (1H,d, J=16 Hz), 7.18-7.28 (3H, m), 7.33 (1H, s), 7.57 (1H, d, J=16 Hz),7.89 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz).

MS (ES+) m/z 387 (M+1).

Preparation 446

1) To a solution of ethyl(2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(591 mg) in dioxane (15 mL) was added 1N sodium hydroxide (4.40 mL).After stirring at 60° C. for 2 hours, the reaction mixture was added H₂O(15 mL) and neutrized with 1N hydrochloric acid (to pH 7). A resultingmixture was evaporated in vacuo.

2) To a mixture of above product,O-tetrahydro-2H-pyran-2-ylhydroxylamine (259 mg), and1-hydroxybenzotriazole (299 mg) in N,N-dimethylformamide (7.4 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (424mg). The mixture was stirred for 6 hours at room temperature. Thereaction mixture was added saturated NaHCO₃ (8 mL) and water (30 mL),and extracted with ethyl acetate. The organic layer was dried overMgSO₄, filtered, and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel to give(2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.48-1.74 (6H, m), 1.82-2.31 (2H, m),3.25-4.02 (6H, m), 4.31-4.50 (1H, m), 4.90 (1H, brs), 6.57-6.69 (1H, m),7.33-8.19 (7H, m), 11.2 (1H, brs).

MS (ES+) m/z 472 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 446.

Preparation 447

(2E)-3-(5-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.46-1.74 (7H, m), 2.11-2.28 (1H, m), 2.22(3H, s), 2.23 (3H, s), 2.34-2.53 (2H, m), 2.59-2.83 (2H, m), 3.30-3.60(3H, m), 3.90-4.01 (1H, m), 4.23-4.35 (1H, m), 4.89 (1H, brs), 6.59 (1H,d, 3=16 Hz), 6.97-7.11 (3H, m), 7.37 (1H, d, J=16 Hz), 7.75 (1H, d, J=6Hz), 7.97 (1H, s), 8.09 (1H, s).

MS (ES+) m/z 452 (M+1).

Preparation 448

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.47-1.74 (7H, m), 2.18-2.31 (1H, m),2.44-2.56 (2H, m), 2.69-2.89 (2H, m), 3.48-3.57 (1H, m), 3.65-3.77 (2H,m), 3.90-4.01 (1H, m), 4.27-4.39 (1H, m), 4.89 (1H, brs), 6.60 (1H, d,J=16 Hz), 7.24-7.54 (5H, m), 7.80 (1H, d, J=6 Hz), 7.98 (1H, s), 8.10(1H, s), 11.2 (1H, brs).

MS (ES+) m/z 458 (M+1).

Preparation 449

(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.46-1.74 (7H, m), 2.17-2.30 (1H, m),2.38-2.48 (2H, m), 2.63-2.81 (2H, m), 3.48-3.57 (1H, m), 3.60 (2H, s),3.89-4.01 (1H, m), 4.25-4.37 (1H, m), 4.89 (1H, brs), 6.60 (1H, d, J=16Hz), 7.26-7.42 (5H, m), 7.79 (1H, d, J=6 Hz), 7.98 (1H, s), 8.10 (1H,s), 11.2 (1H, brs).

MS (ES+) m/z 458 (M+1).

Preparation 450

To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg) and3-methoxybenzaldehyde (352 uL) in CH₂Cl₂ (4.5 mL) was added sodiumtriacetoxyborohydride (922 mg), which was stirred at room temperaturefor 2 hours. To the resultant was added sat. NaHCO₃ aq., which wasstirred for 20 min. The mixture was extracted with CH₂Cl₂. The organicphase was washed with brine and dried over Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to give tert-butyl[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (744 mg) as aoff-white solid.

¹H NMR (200 MHz, CDCl₃) d 1.43 (9H, s), 1.49-1.72 (1H, m), 2.16-2.46(2H, m), 2.58-2.72 (2H, m), 2.80-2.98 (1H, m), 3.63 (2H, br. s), 3.82(3H, s), 4.08-4.31 (1H, br), 4.90-5.14 (1H, br), 6.76-6.95 (3H, m), 7.24(1H, t, J=8.1 Hz);

MS (ES+) m/z 307 (M+1).

The following compound was obtained in a similar manner to that ofPreparation 450.

Preparation 451

tert-butyl [(3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]carbamate

¹H NMR (CDCl₃, 200 MHz) d 1.44 (9H, s), 1.50-1.82 (1H, m), 2.12-2.42(2H, m), 2.48-2.72 (2H, m), 2.72-2.89 (1H, m), 3.63 (2H, s), 4.08-4.31(1H, br), 4.70-4.99 (1H, br), 7.36-7.68 (4H, m);

MS (ES+) 302 (M+1).

Preparation 452

To a solution of tert-butyl[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (739 mg) in ethylacetate (3.7 mL) was added 4N HCl-ethyl acetate (6.0 mL), which wasstirred at room temperature for 1.5 hours. The mixture was concentratedto give (3R)-1-(3-methoxybenzyl)-3-pyrrolidinamine dihydrochloride (702mg) as a off-white amorphous.

¹H NMR (DMSO-d6, 200 MHz) δ 1.90-2.42 (2H, m), 3.06-4.16 (5H, m), 3.79(3H, s), 4.34-4.58 (2H, br), 6.95-7.42 (4H, m), 8.47-8.58 (2H, br); MS(ES+) m/z 207 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 452.

Preparation 453

3-{[(3R)-3-amino-1-pyrrolidinyl]methyl}benzonitrile dihydrochloride

¹H NMR(DMSO-d6, 200 MHz) δ 1.89-2.34 (2H, m), 3.05-4.22 (5H, m),4.41-4.71 (2H, m), 7.69 (1H, t, J=7.8 Hz), 7.89-8.23 (3H, m), 8.25-8.82(2H, m);

MS (ES+) m/z 202 (M+1).

Preparation 454

N-(3-{[(3R)-3-amino-1-pyrrolidinyl]methyl}phenyl)acetamidedihydrochloride

¹H NMR (DMSO-d6, 200 MHz) δ 2.06 (3H, s), 1.91-2.35 (2H, m), 3.03-4.19(5H, m), 4.42 (2H, m), 7.23-7.46 (2H, m), 7.49-7.65 (2H, m), 7.82 (1H,s), 8.39-8.85 (3H, m), 10.21 (1H, s), 11.10-11.67 (1H, m); MS (ES+) m/z234 (M+1).

Preparation 455

(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinamine trihydrochloride

¹H NMR (DMSO-d6, 200 MHz) δ 1.94-2.41 (2H, m), 3.03 (6H, s), 3.03-4.18(5H, m), 4.31-4.63 (2H, m), 7.02-7.74 (4H, m), 8.51-9.05 (3H, m),11.29-12.15 (1H, m);

MS (ES+) m/z 220 (M+1).

Preparation 456

N-(3-{[(3R)-3-amino-1-pyrrolidinyl]methyl}phenyl)methanesulfonamidedihydrochloride

¹H NMR (DMSO-d6, 200 MHz) δ 1.95-2.37 (2H, m), 3.10 (3H, s), 3.11-4.17(5H, m), 4.32-4.58 (2H, br), 6.93-7.51 (4H, m, J=q Hz), 8.34-8.94 (3H,m), 10.00 (1H, s), 11.16-11.98 (1H, m);

MS (ES+) m/z 270 (M+1).

Preparation 457

To a mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (278 mg) in1,3-dimethyl-2-imidazolidinone (2.78 mL) was added(3R)-1-(3-methoxybenzyl)-3-pyrrolidinamine dihydrochloride (547.5 mg)and K₂CO₃ (1.08 g), which was stirred at 106° C. for 3 hours. To theresultant was added H₂O, which was extracted with ethyl acetate. Theorganic phase was washed with brine, dried over Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to give ethyl(2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(367.5 mg) as a brown solid.

¹H NMR(CDCl₃, 200 MHz) δ 1.32 (3H, t, J=7.1 Hz), 1.62-1.86 (1H, m),2.28-2.50 (2H, m), 2.72 (2H, d, J=4.6 Hz), 2.89-3.04 (1H, m), 3.6.6 (2H,s), 3.81 (3H, s), 4.25 (2H, q, J=7.1 Hz), 4.39-4.58 (1H, m), 5.29-5.44(1H, m), 6.68 (1H, d, J=15.5 Hz), 6.74-6.96 (3H, m), 7.25 (1H, t, J=7.9Hz), 7.57 (1H, d, J=15.5 Hz), 7.89 (1H, d, J=1.2 Hz), 8.22 (1H, d, J=1.2Hz);

MS (ES+) m/z 383 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 457.

Preparation 458

ethyl(2E)-3-(5-{[(3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H NMR δ (DMSO-d6, 400 MHz) d 1.24 (3H, t, J=7.0 Hz), 1.62-1.72 (1H, m),2.18-2.30 (1H, m), 2.39-2.48(2H, m), 2.64-2.73 (1H, m), 2.75-2.83 (1H,m), 3.66 (2H, s), 4.17 (2H, q, J=7.12 Hz), 4.34 (1H, br), 6.50 (1H, d,J=15.6 Hz), 7.50-7.58 (2H, m), 7.65-7.79 (3H, m), 7.92-7.79 (1H, m),8.00 (1H, s), 8.21 (1H, s);

MS (ES+) m/z 378 (M+1).

Preparation 459

ethyl(2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylate

¹H NMR (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.2 Hz), 1.60-1.71 (1H, m),2.02 (3H, s), 2.16-2.29 (1H, m), 2.31-2.53 (2H, m), 2.59-2.68 (1H, m),2.75-2.83 (1H, m), 3.54 (2H, s), 4.16 (2H, q, J=7.1 Hz), 4.26-4.37 (1H,m), 6.49 (1H, d, J=15.5 Hz), 6.97 (1H, d, J=7.5 Hz), 7.21 (1H, t, J=7.8Hz), 7.45 (1H, d, J=8.2 Hz), 7.49-7.57 (2H, m), 7.92 (1H, d, J=6.6 Hz),7.99 (1H, s), 8.20 (1H, s), 9.89 (1H, s);

MS (ES+) m/z 410 (M+1).

Preparation 460

ethyl(2E)-3-[5-({(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylate

¹H NMR (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.2 Hz), 1.60-1.71 (1H, m),2.17-2.28 (1H, m), 2.38-2.57 (2H, m), 2.63-2.78 (2H, m), 2.86 (6H, s),3.49 (1H, d, J=12.9 Hz), 3.54 (1H, d, J=12.9 Hz), 4.16 (2H, q, J=7.12Hz), 4.26-4.39 (1H, m), 6.49 (1H, d, J=15.6 Hz), 6.56-6.68 (3H, m), 7.10(1H, t, J=7.8 Hz), 7.52 (1H, d, J=15.6 Hz), 7.90-7.97 (1H, m), 7.99 (1H,d, J=1.0 Hz), 8.20 (1H, d, J=1.1 Hz);

MS (ES+) m/z 396 (M+1).

Preparation 461

ethyl(2E)-3-(5-{[(3R)-1-{3-[(methylsulfonyl)amino]benzyl}-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H NMR (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.0 Hz), 1.59-1.72 (1H, m),2.16-2.29 (1H, m), 2.37-2.53 (2H, m), 2.61-2.70 (1H, m), 2.74-2.82 (1H,m), 2.94 (3H, s), 3.50-3.61 (2H, m), 4.16 (2H, q, J=7.1 Hz), 4.25-4.37(1H, m), 6.49 (1H, d, J=15.4 Hz), 7.00-7.11 (2H, m), 7.16 (1H, s), 7.26(1H, t, J=7.7 Hz), 7.53 (1H, d, J=15.6 Hz), 7.93 (1H, d, J=6.5 Hz), 7.99(1H, d, J=1.0 Hz), 8.20 (1H, d, J=1.1 Hz), 9.20-9.70 (1H, br);

MS (ES+) 446 (M+1).

Preparation 462

To a solution of ethyl(2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(362 mg) in methanol (2.9 mL) was added 1N NaOH aq. (947 uL), which wasstirred at 55° C. for 45 minutes. The reaction mixture was added 1N HClaq. (947 uL), and evaporated in vacuo to give(2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid, which was used in the next step without further purification.

The following compounds were obtained in a similar manner to that ofPreparation 462.

Preparation 463

(2E)-3-(5-{[(3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

Preparation 464

(2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylicacid

Preparation 465

(2E)-3-[5-({(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylicacid

Preparation 466

(2E)-3-(5-{[(3R)-1-(3-[(methylsulfonyl)amino]benzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

Preparation 467

(2E)-3-(5-{[(3R)-1-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

Preparation 468

(2E)-3-(5-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

Preparation 469

(2E)-3-(5-{[(3R)-1-(3-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

Preparation 470

(2E)-3-(5-{[(3R)-1-(3-isopropoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

Preparation 471

To a mixture of(2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid (crude of reaction), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine(166.4 mg), and 1-hydroxybenzotriazole (191.9 mg) in DMF (3.4 mL) wasadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (251 uL), which wasstirred at room temperature for 16.5 hours. To the resultant was addedsat. NaHCO₃ aq. The mixture was extracted with CH₂Cl₂. The organic phasewas washed with brine, dried over Na₂SO₄, filtered, and evaporated invacuo. The residue was purified by column chromatography on silica gelto give(2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(312 mg) as a yellow amorphous.

¹H NMR (200 MHz, DMSO-d6) δ 1.42-1.83 (7H, m), 2.12-2.34 (1H, m),2.37-2.57 (2H, m), 2.58-2.88 (2H, m), 3.44-3.63 (3H, m), 3.73 (3H, s),3.84-4.08 (1H, m), 4.12-4.42 (1H, m), 4.89 (1H, br), 6.59 (1H, d, J=15.0Hz), 6.73-6.96 (3H, m), 7.22 (1H, t, J=7.9 Hz), 7.37 (1H, d, J=15.3 Hz),7.77 (1H, d, J=6.8 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.17 (1H, br); MS(ES+) m/z 454 (M+1))

The following compounds were obtained in a similar manner to that ofPreparation 471.

Preparation 472

(2E)-3-(5-{[(3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.45-1.60 (3H, m), 1.60-1.80 (4H, m),2.17-2.30 (1H, m), 2.39-2.48 (2H, m), 2.64-2.73 (1H, m), 2.74-2.83 (1H,m), 3.46-3.57 (1H, m), 3.66 (2H, s), 3.89-4.01 (1H, br), 4.23-4.39 (1H,br), 4.90 (sH, s), 6.69 (1H, d, J=15.1 Hz), 7.38 (1H, d, J=15.4 Hz),7.54 (1H, t, J=7.7 Hz), 7.68 (1H, d, J=7.8 Hz), 7.73 (1H, d, J=7.7 Hz),7.74-7.83 (2H, m), 7.98 (1H, s), 8.10 (1H, s), 11.18 (1H, s);

MS (ES+) m/z 449 (M+1).

Preparation 473

(2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.45-1.77 (7H, m), 1.02 (3H, s), 2.16-2.29(1H, m), 2.33-2.40 (1H, m), 2.41-2.53 (1H, m), 2.58-2.69 (1H, m),2.75-2.84 (1H, m), 3.47-3.60 (3H, m), 3.88-4.02 (1H, m), 4.21-4.38 (1H,m), 4.89 (1H, s), 6.60 (1H, d, J=15.1 Hz), 6.97 (1H, d, J=7.6 Hz), 7.21(1H, t, J=7.8 Hz), 7.37 (1H, d, J=15.2 Hz), 7.45 (1H, d, J=8.1 Hz), 7.54(1H, s), 7.77 (1H, d, J=6.3 Hz), 7.96 (1H, s), 8.09 (1H, s), 9.90 (1H,s), 11.18 (1H, s);

MS (ES+) m/z 481 (M+1).

Preparation 474

(2E)-3-(5-{[(3R)-1-{3-[(methylsulfonyl)amino]benzyl}-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.44-1.78 (7H, m), 2.15-2.28 (1H, m),2.31-2.57 (2H, m), 2.61-2.71 (1H, m), 2.73-2.83 (1H, m), 2.94 (3H, s),3.48-3.61 (3H, m), 3.88-4.00 (1H, m), 4.24-4.36 (1H, m), 4.89 (1H, s),6.59 (1H, d, J=15.2 Hz), 7.01-7.11 (2H, m), 7.16 (1H, s), 7.26 (1H, t,J=7.8 Hz), 7.37 (1H, d, J=15.2 Hz), 7.77 (1H, d, J=6.3 Hz), 7.97 (1H,s), 8.09 (1H, s), 9.55-9.85 (1H, br), 11.07-11.29 (1H, br); MS (ES+) m/z517 (M+1).

Preparation 475

(2E)-3-[5-({(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.42-1.77 (7H, m), 2.13-2.28 (1H, m),2.34-2.57 (2H, m), 2.62-2.78 (2H, m), 2.86 (6H, s), 3.43-3.58 (3H, m),3.89-4.01 (1H, m), 4.24-4.34 (1H, m), 4.89 (1H, s), 6.54-6.67 (4H, m),7.10 (1H, t, J=8.0 Hz), 7.36 (1H, d, J=15.2 Hz), 7.77 (1H, d, J=6.5 Hz),7.97 (1H, s), 8.09 (1H, s), 11.18 (1H, s);

MS (ES+) m/z 467 (M+1).

Preparation 476

(2E)-3-(5-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.44-1.77 (7H, m), 2.13-2.28 (1H, m),2.40-2.55 (2H, m), 2.65-2.74 (1H, m), 2.74-2.81 (1H, m), 3.48-3.65 (3H,m), 3.77 (3H, s), 3.89-4.00 (1H, m), 4.25-4.36 (1H, m), 4.89 (1H, s),6.59 (1H, d, J=15.1 Hz), 6.91 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=8.2 Hz),7.24 (1H, t, J=7.3 Hz), 7.31 (1H, d, J=7.4 Hz), 7.37 (1H, d, J=15.4 Hz),7.77 (1H, d, J=6.3 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.17 (1H, s);

MS (ES+) m/z 454 (M+1).

Preparation 477

(2E)-3-(5-{[(3R)-1-(3-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.41-1.79 (7H, m), 2.15-2.29 (1H, m),2.33-2.48 (2H, m), 2.59-2.69 (1H, m), 2.73-2.81 (1H, m), 3.40-3.56 (3H,m), 3.87-4.00 (1H, m), 4.24-4.35 (1H, m), 4.83-4.93 (1H, m), 6.54-6.66(2H, m), 6.66-6.77 (2H, m), 7.08 (1H, t, J=8.1 Hz), 7.37 (1H, d, J=15.2Hz), 7.76 (1H, d, J=6.4 Hz), 7.97 (1H, s), 8.09 (1H, s), 9.29 (1H, s),11.17 (1H, br);

MS (ES+) m/z 440 (M+1).

Preparation 478

(2E)-3-(5-{[(3R)-1-(3-isopropoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.20-1.27 (6H, m), 1.47-1.76 (7H, m),2.14-2.28 (1H, m), 2.37-2.47 (2H, m), 2.63-2.77 (2H, m), 3.47-3.61 (3H,m), 3.89-4.00 (1H, m), 4.25-4.35 (1H, m), 4.56 (1H, septet, J=6.0 Hz),4.89 (1H, s), 6.59 (1H, d, J=15.2 Hz), 6.77 (1H, d, J=7.8 Hz), 6.82-6.87(2H, m), 7.19 (1H, t, J=8.0 Hz), 7.37 (1H, d, J=15.2 Hz), 7.77 (1H, d,J=6.2 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.17 (1H, s); MS (ES+) m/z 482.

Preparation 479

(2E)-3-(5-{[(3R)-1-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, 400 MHz) δ 1.44-1.79 (7H, m), 2.19-2.35 (1H, m),2.44-2.56 (2H, m), 2.71-2.86 (2H, m), 3.12-3.60 (3H, m), 3.87-4.01 (1H,m), 4.27-4.39 (1H, m), 4.82-4.92 (1H, m), 6.62 (1H, d, J=15.2 Hz),6.69-6.80 (3H, m), 7.00-7.14 (2H, m), 7.38 (1H, d, J=15.3 Hz), 7.77-7.87(1H, m), 7.98 (1H, s), 8.10 (1H, s), 11.17 (1H, br);

MS (ES+) m/z 440 (M+1).

Preparation 480

To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg),1-(chloromethyl)-3-nitrobenzene (435 mg) in DMF (4.5 mL) was addedN,N-diisopropylamine (463 uL), which was stirred at 75° C. for 4 hours.To the resultant was added H₂O. The mixture was extracted with ethylacetate. The organic phase was washed brine, dried over Na₂SO₄,filtered, and evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give tert-butyl[(3R)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (, 757 mg) as a orangeoil.

¹H NMR (200 MHz, CDCl₃) δ 1.44 (9H, s), 1.50-1.77 (1H, m), 2.17-2.96(5H, m), 3.60-3.80 (2H, m), 4.19 (1H, br), 4.84 (1H, br), 7.49 (1H, t,J=7.9 Hz), 7.68 (1H, d, J=7.4 Hz), 7.99-8.24 (2H, m);

MS (ES+) 322 (M+1).

Preparation 481

tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate

To a solution of tert-butyl[(3R)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (750 mg) in ethanol(5.6 mL) and H₂O (1.9 mL) was added NH₄Cl (62.4 mg) and Fe (391 mg),which was stirred under reflux for 1 hour. The resultant was filteredand evaporated in vacuo. The residue was washed water and brine. Theorganic layer was dried over Na₂SO₄, filtered, and evaporated in vacuoto give tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (645mg) as a brown oil.

¹H NMR(CDCl₃, 200 MHz) δ 1.43 (9H, s), 1.48-1.71 (1H, m), 2.12-2.43 (2H,m), 2.44-3.00 (3H, m), 3.51 (2H, s), 3.65 (2H, br), 4.17 (1H, br), 4.88(1H, br), 6.53-6.73 (3H, m), 7.09 (1H, t, J=7.9 Hz); API-ES(posi) 292(M+1).

Preparation 482

To a solution of tert-butyl[(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (640 mg) in CH₂Cl₂ (6.4mL) was added 35% HCHO ag. (1.42 mL) and sodium triacetoxyborohydride(1.4 g), which was stirred at room temp temperature at 24 hours. To theresultant was added sat. NaHCO₃ aq., which was stirred for 20 min. Themixture was extracted with ethyl acetate. The organic phase was washedby brine, dried over Na₂SO₄, filtered, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel to givetert-butyl {(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl}carbamate(365 mg) as a white solid.

¹H NMR(CDCl₃, 200 MHz) δ 1.43 (9H, s), 1.50-1.76 (1H, m), 2.12-2.44 (2H,m), 2.47-2.70 (2H, m), 2.72-2.93 (1H, m), 2.95 (6H, s), 3.57 (2H, s),4.17 (1H, br), 4.90 (1H, br), 6.58-6.74 (3H, m), 7.18 (1H, t, J=7.7 Hz);

MS (ES+) m/z 320 (M+1).

Preparation 483

To a solution of tert-butyl[(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (681 mg) in CH₂Cl₂ (6.8mL) was added pyridine (28:4 uL), acetic anhydride (265 uL), andN,N-dimethylaminopyridine (14 mg), which was stirred at room temperaturefor 1.5 hours. To the resultant was added H₂O. The mixture was extractedwith CH₂Cl₂. The organic phase was washed by brine, dried over Na₂SO₄,filtered, and evaporated in vacuo to give tert-butyl{(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}carbamate (944 mg) as aoff-white amorphous.

¹H NMR(CDCl₃, 200 MHz) δ 1.42 (9H, s), 1.71-2.00 (1H, m), 2.18 (3H, s),36-2.47 (1H, m), 2.58-2.75 (1H, m), 2.78-3.07 (2H, m), 3.07-3.36 (1H,m), 3.86 (2H, s), 4.34 (1H, br), 5.06 (1H, br), 7.10 (1H, d, J=7.5 Hz),7.30 (1H, t, J=7.6 Hz), 7.56-7.69 (2H, m), 7.81 (1H, br);

MS (ES+) m/z 334 (M+1).

Preparation 484

To tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]carbamate (3.0 g)was added 4NHCl/Dioxane (38 ml) at room temperature.

The mixture was stirred for 2 hrs at the same temperature.

Evaporated and decantated with diisopropyl ether (three times).

Evaporated to give 2.85 g of (3R)-1-(3-fluorobenzyl)-3-pyrrolidinaminedihydrochloride as an amorphous.

MASS (ESI+): m/z=195.2 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 2.00-2.42 (2H, m), 3.00-4.20 (6H, m),4.40-4.64 (2H, br.s), 7.20-7.40 (1H, m), 7.40-7.70 (3H, m), 8.67 and8.84 (3H, br.s).

Preparation 485

To a solution of tert-butyl[(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (659 mg) in CH₂Cl₂ (6.6mL) was added pyridine (274 uL) and methanesulfonyl chloride (193 uL),which was stirred at room temperature for 20 hours. To the resultant wasadded H₂O. The mixture was extracted with 1-butanol. The organic phasewas washed brine, dried Na₂SO₄, filtered, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel to givetert-butyl[(3R)-1-{3-[(methylsulfonyl)amino]benzyl)-3-pyrrolidinyl]carbamate (845mg) as pale yellow amorphous.

¹H NMR (CDCl₃. 200 MHz) δ 1.43 (9H, s), 1.44-1.78 (1H, m), 2.16-2.46(2H, m), 2.50-2.76 (2H, m), 2.78-2.95 (1H, m), 3.02 (3H, s), 3.62 (2H,s), 4.20 (1H, br), 4.93 (1H, br), 7.08-7.36 (4H, m);

MS(ES+) m/z 370.3 (M+1).

Preparation 486

To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (2.0 g) and2-fluorobenzaldehyde (1.4 g) was added NaBH(OAc)₃ 2.73 g (1.2 eq) underice-cooling.

After 30 min, the mixture was allowed to warm to room temperature andstirred for 8 hrs.

Dichloromethane and water was added. Separated organic layer. Extractedwith dichloromethane. sat. aq. NaHCO₃ was added to combined organiclayer.

Separated organic layer. Dried with Na₂SO₄.

Evaporated to give 3.21 g of tert-butyl[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]carbamate.

MASS (ESI+): m/z 295.3 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.43 (9H, s), 1.5-1.7 (1H, m), 2.2-2.9 (5H,m), 3.67 (2H, s), 4.17 (1H, br.s), 4.87 (1H, br.s), 7.00-7.05 (1H, m),7.08-7.12 (1H, m), 7.21-7.24 (1H, m), 7.33-7.37 (1H, m).

Preparation 487

To tert-butyl [(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]carbamate (3.0 g)was added 4NHCl/Dioxane (38 ml) at room temperature.

The mixture was stirred for 2 hrs at the same temperature.

Evaporated and decantated with diisopropyl ether (three times).

Evaporated to give 3.74 g of (3R)-1-(2-fluorobenzyl)-3-pyrrolidinaminedihydrochloride.

MASS (ESI+): m/z=195.2 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 2.0-2.6 (2H, m), 3.18-4.15 (4H, m), 3.57 (s,2H), 4.52 (2H, br.s), 7.29-7.36 (2H, m), 7.50-7.56 (1H, m), 7.70-7.80(1H, m), 8.63 and 8.76 (3H, br.s).

Preparation 488

A mixture of (3R)-1-(3-fluorobenzyl)-3-pyrrolidinamine dihydrochloride(1.0 g), methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.74 g) andNa₂CO₃ (4.18 g) was stirred under heating condition (oil bathtemperature: 206° C.).

After 8 hours, the reaction mixture was added to ice water and extractedwith CHCl₃.

Aqueous layer was extracted with CHCl₃ (twice).

Combined organic layer was washed with water (three times), dried overMgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel (Hex:EtOAc toCHCl₃:MeOH=8:1) to give 1.68 g (94%) of methyl(2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylateas an oil.

MASS (ESI+): m/z=357.2 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.70-1.80 (1H, m), 2.35-2.50 (2H, m),2.65-2.75 (2H, m), 2.79 (3H, s), 2.90-3.00 (1H, m), 3.65 (2H, s), 4.50(1H, br.s), 5.45 (1H, d, J=6.6 Hz), 6.68 (1H, d, J=15.6 Hz), 6.95-7.35(4H, m), 7.58 (1H, d, J=15.6 Hz), 7.90 (1H, d, J=1.28 Hz), 8.03 (1H, d,J=1.28 Hz).

Preparation 489

To a solution of methyl(2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(1.98 g) in methanol (42 ml) was added 1NNaOH (21 ml) at roomtemperature. After stirring for 2 hrs, 1N HCl (21 ml) was added. Themixture was evaporated under reduced pressure. To a residue was addedDMF (40 ml), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (815 mg), HOBt(940 mg) and WSCD (1.25 g) at room temperature. After stirring for 12hrs, water was added, the mixture was extracted with CHCl₃ (3 times),and organic layer was washed with water (twice), dried over Na₂SO₄,filtered and evaporated.

The residue was column chromatographed on silica gel (Hex EtOAc toCHCl₃:MeOH) to give crude product.

The crude product was purified with HPLC (Yamazene packed column 26×100mm) to give 730 mg (30%) of(2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamideas an oil.

MASS (ESI+): m/z=442.3 (M+1).

MASS (ESI−): m/z=440.4 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.51-2.03 (7H, m), 2.33-2.46 (2H, m), 2.71(2H, d, J=4.8 Hz), 2.90-2.97 (1H, m), 3.65 (2H, s), 3.96 (1H, t, J=9.8Hz), 4.44-4.53 (1H, m), 5.01 (1H, br.s), 5.38 (1H, d, J=8.0 Hz), 6.96(1H, dt, J=2.5 and 8.4 Hz), 7.04-7.12 (2H, m), 7.27 (1H, s), 7.25-7.31(1H, m), 7.61 (1H, d, J=15.1 Hz), 7.87 (1H, s), 8.02 (1H, s).

Preparation 490

A mixture of (3R)-1-(2-fluorobenzyl)-3-pyrrolidinamine dihydrochloride(1.0 g), methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.74 g) andNa₂CO₃ (4.18 g) was stirred under heating condition (oil bathtemperature: 206° C.).

After 8 hours, the reaction mixture Was added to ice water and extractedwith CHCl₃.

Aqueous layer was extracted with CHCl₃ (twice).

Combined organic layer was washed with water (three times), dried overMgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel (Hex:EtOAc toCHCl₃:MeOH=8:1) to give 1.22 g (68%) of methyl(2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylateas an oil.

MASS (ESI+): m/z=357.2 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.61-1.84 (1H, m), 2.25-3.00 (m, 5H), 3.79(2H, s), 4.45-4.53 (1H, m), 5.45 (1H, d, J=6.6 Hz), 6.68 (1H, d, J=15.6Hz), 7.00-7.45 (4H, m), 7.27 (2H, s), 7.57 (1H, d, J=15.6 Hz), 7.88 (1H,d, J=1.28 Hz), 8.03 (1H, d, J=1.28 Hz).

Preparation 491

To a solution of methyl(2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(1.20 g) in methanol (34 ml) was added 1NNaOH (16.9 ml) at roomtemperature and stirred for 2 hrs. After then, the reaction mixture wasneutralized with 1N HCl (16.9 ml).

The mixture was evaporated under reduced pressure and co-evaporated withtoluene (twice).

To the residue in DMF (30 ml) was addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (513 mg), HOBt (591 mg) andWSCD (784 mg) and the mixture was stirred overnight.

After 12 hours, water was added and extracted with CHCl₃ (Three times).

Combined organic layer was washed with water, dried over Na₂SO₄,filtered and evaporated.

The reside was column chromatographed on silica gel (Hex:EtOAc to CHCl₃MeOH) to give crude(2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide.

Crude product was purified with HPLC (Yamazene packed column, 26 mm×100mm) to give 540 mg (36%) of(2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamideas an oil.

MASS (ESI+): m/z=442.3 (M+1).

¹HNMR (400 MHz): δ 1.56-2.13 (7H, m), 2.26-2.53 (2H, m), 2.63-3.06 (3H,m), 3.57-3.83 (3H, m), 3.97 (1H, m), 4.49 (1H, m), 5.01 (1H, br.s), 5.46(1H, m), 7.05 (1H, ddd, J=1.0, 8.2 and 9.8 Hz), 7.12 (1H, dt, J=1.2 and7.5 Hz), 7.22-7.30 (1H, m), 7.26 (2H, s), 7.38 (1H, dt, J=1.6 and 7.5Hz), 7.61 (1H, d, J=14.1 Hz), 7.85 (1H, s), 8.02 (1H, s).

Preparation 492

To a suspension of methyl(2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl)acrylatedihydrochloride (260 mg) in CH₂Cl₂ (2.6 mL) was addedN,N-diisopropylethylamine (282 uL), 2-methoxybenzaldehyde (121.2 mg),and sodium triacetoxyborohydride (343 mg), which was stirred at roomtemperature for 1 hour. To the resultant was added sat. NaHCO₃ aq.,which was stirred for 20 min. The mixture was extracted with CH₂Cl₂. Theorganic phase was washed with brine and dried over Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to give methyl(2E)-3-(5-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate(193 mg) as a yellow amorphous.

¹H NMR (DMSO-d6, 400 MHz) δ 1.59-1.70 (1H, m), 2.16-2.28 (1H, m),2.40-2.53 (2H, m), 2.65-2.74 (1H, m), 2.74-2.81 (1H, m), 3.53-3.64 (2H,m), 3.69 (3H, s), 3.77 (3H, s), 4.26-4.38 (1H, m), 6.51 (1H, d, J=15.4Hz), 6.91 (1H, t, J=7.4 Hz), 6.96 (1H, d, J=8.2 Hz), 7.22 (1H, t, J=8.2Hz), 7.31 (1H, d, J=7.2 Hz), 7.55 (1H, d, J=15.6 Hz), 7.95 (1H, d, J=6.6Hz), 8.00 (1H, s), 8.21 (1H, s);

MS (ES+) m/z 369 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 492.

Preparation 493

methyl(2E)-3-(5-{[(3R)-1-(3-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H NMR (DMSO-d6, 400 MHz) δ 1.60-1.71 (1H, m), 2.16-2.28 (1H, m),2.32-2.47 (2H, m), 2.59-2.69 (1H, m), 2.73-2.81 (1H, m), 3.49 (2H, s),3.69 (3H, s), 4.25-4.37 (1H, m), 6.51 (1H, d, J=15.4 Hz), 6.62 (1H, d,J=7.0 Hz), 6.67-6.79 (2H, m), 7.08 (1H, t, J=8.0 Hz), 7.55 (1H, d,J=15.4 Hz), 7.94 (1H, d, J=6.5 Hz), 8.00 (1H, s), 8.20 (1H, s), 9.28(1H, s);

MS (ES+) m/z 355 (M+1).

Preparation 494

methyl(2E)-3-(5-{[(3R)-1-(3-isopropoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H NMR (DMSO-d6, 400 MHz) δ 1.18-1.31 (6H, m), 1.61-1.73 (1H, m),2.16-2.29 (1H, m), 2.37-2.47 (2H, m), 2.61-2.79 (2H, m), 3.52 (1H, d,J=13.1 Hz), 3.57 (1H, d, J=13.2 Hz), 3.69 (3H, s), 4.23-4.38 (1H, m),4.56 (1H, septet, J=6.0 Hz), 6.51 (1H, d, J=15.5 Hz), 6.77 (1H, dd,J=2.0, 8.0 Hz), 6.80-6.90 (2H, m), 7.19 (1H, t, J=8.0 Hz), 7.55 (1H, d,J=15.5 Hz), 7.94 (1H, d, J=6.7 Hz), 8.00 (1H, d, J=2.4 Hz), 8.20 (1H,s);

MS (ES+) m/z 397 (M+1).

Preparation 495

methyl(2E)-3-(5-{[(3R)-1-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H NMR (DMSO-d6, 400 MHz) δ 1.66-1.79 (1H, m), 2.19-2.35 (1H, m),2.43-2.58 (2H, m), 2.72-2.88 (2H, m), 3.70 (3H, s), 3.71 (2H, s),4.27-4.42 (1H, m), 6.52 (1H, d, J=15.5 Hz), 6.67-6.79 (2H, m), 7.02-7.15(2H, m), 7.56 (1H, d, J=15.5 Hz), 7.95-8.04 (2H, m), 8.21 (1H, d, J=1.1Hz);

MS (ES+) m/z 355 (M+1).

Preparation 496

To a solution of methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (680 mg)in DMI (1.4 mL) was added tert-butyl(3R)-3-amino-1-pyrrolidinecarboxylate (957 mg) and K₂CO₃ (1.42 g), whichwas stirred at 120° C. for 2 hours. The reaction mixture was filteredand evaporated in vacuo. To the residue was added H₂O, which wasextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue waspurified by column chromatography on silica gel to give tert-butyl(3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate(834 mg) as a off-white powder.

¹H NMR (400 MHz, CDCl₃) δ 1.47 (9H, s), 1.88-2.03 (1H, br), 2.20-2.33(1H, m), 3.19-3.40 (1H, m), 3.41-3.58 (2H, m), 3.69-3.77 (1H, m), 3.80(3H, s), 4.51 (1H, br), 5.08 (1H, br), 6.72 (1H, d, J=15.5 Hz), 7.60(1H, d, J=15.6 Hz), 7.95 (1H, d, J=1.3 Hz), 8.08 (1H, s);

MS (ES+) m/z 371 (M+23).

Preparation 497

To a solution of tert-butyl(3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate(830 mg) in dioxane (8.3 mL) was added 4N HCl/dioxane (6.0 mL), whichwas stirred at room temperature for 1 hour. To the reaction mixture wasadded diisopropylether, and the precipitate was filtered to give methyl(2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylatedihydrochloride (742 mg) as a yellow powder.

¹H NMR (DMSO-d6, 400 MHz) δ 1.92-2.02 (1H, m), 2.16-2.28 (1H, m),3.05-3.15 (1H, m), 3.21-3.49 (3H, m), 3.71 (3H, s), 4.43-4.52 (1H, br),6.57 (1H, d, J=15.7 Hz), 7.60 (1H, d, J=15.6 Hz), 8.07 (1H, d, J=1.1Hz), 8.23-8.39 (2H, m), 9.43 (2H, br);

MS (ES+) m/z 249 (M+1).

Preparation 498

To a solution of ethyl(2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (47mg) in dioxane (1.4 mL) was added 1N sodium hydroxide (0.42 mL). Afterstirring at 60° C. for 2 hours, the reaction mixture was added H₂O (7mL) and acidified with 1N hydrochloric acid (to pH 4). A resultingprecipitate was collected by filtration, and washed with water to give(2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acidhydrochloride (39 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 1.93-2.05 (1H, m), 2.23-2.36 (1H, m),3.09-3.64 (4H, m), 4.54-4.62 (1H, m), 6.25 (1H, d, J=16 Hz), 6.51-6.63(4H, m), 7.12-7.21 (2H, m), 7.44-7.51 (2H, m), 7.79 (1H, d, J=9 Hz),8.24 (1H, brs), 12.1 (1H, brs).

MS (ES+) m/z 310 (M+1).

Preparation 499

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-nitrophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(297 mg) in ethanol (3 mL) was added tin(II) chloride (583 mg), and themixture was heated at reflux for 6 hours. After cooling, the reactionmixture was basified with 2N sodium hydroxide and extracted with ethylacetate. The organic layer was dried over Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to give ethyl(2E)-3-(6-{[(3R)-1-(4-aminophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(186 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.97-2.08 (1H, m),2.32-2.45 (1H, m), 3.19-3.61 (4H, m), 4.25 (2H, q, J=7 Hz), 4.53-4.64(1H, m), 4.96-5.00 (1H, m), 6.23 (1H, d, J=16 Hz), 6.41 (1H, d, J=9 Hz),6.49 (2H, d, J=9 Hz), 6.68 (2H, d, J=9 Hz), 7.58 (1H, d, J=16 Hz), 7.63(1H, dd, J=2, 9 Hz), 8.22 (1H, d, J=2 Hz),

MS (ES+) m/z 353 (M+1).

Preparation 500

To a mixture of ethyl(2E)-3-(6-{[(3R)-1-(4-aminophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(178 mg) and 50% phosphinic acid (5 mL) was added sodium nitrite (62.7mg) in H₂O at 4° C. The reaction mixture was stirred for 2 hours at 4°C. The resulting mixture was neutrized with saturated NaHCO₃ andextracted with chloroform. The organic layer was dried over MgSO₄,filtered, and evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give ethyl(2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(49.0 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 2.01-2.13 (1H, m),2.34-2.47 (1H, m), 3.25-3.74 (4H, m), 4.25 (2H, q, J=7 Hz), 4.57-4.67(1H, m), 4.91-4.97 (1H, m), 6.24 (1H, d, J=16 Hz), 6.42 (1H, d, J=9 Hz),6.59 (2H, d, J=9 Hz), 6.69-6.76 (1H, m), 7.22-7.30 (2H, m), 7.58 (1H, d,J=16 Hz), 7.63 (1H, dd, J=2, 9 Hz), 8.23 (1H, d, J=2 Hz).

MS (ES+) m/z 338 (M+1).

Preparation 501

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylatedihydrochloride (268 mg) in DMF (3 mL) was added 1-fluoro-4-nitrobenzene(91.4 mg) and N,N-diisopropylethylamine (0.376 mL). After stirring for 3hours at 120° C., the reaction mixture was partitioned between ethylacetate and H₂O. The organic layer was washed with H₂O and brine, driedover MgSO₄, filtered, and evaporated in vacuo to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-nitrophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(299 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7 Hz), 1.45 (9H, s), 2.27-2.48(2H, m), 3.33-3.52 (2H, m), 3.67-3.82 (2H, m), 4.28 (2H, q, J=7 Hz),5.06-5.18 (1H, m), 6.44 (2H, d, J=9 Hz), 6.45 (1H, d, J=16 Hz), 7.32(1H, d, J=8 Hz), 7.63 (1H, d, J=16 Hz), 7.83 (1H, dd, J=2, 8 Hz), 8.11(2H, d, J=9 Hz), 8.50 (1H, d, J=2 Hz),

MS (ES+) m/z 483 (M+1).

Preparation 502

1) To a mixture of 6-chloro-3-pyridazinecarbaldehyde (500 mg) and THF(10 mL) was added (carbethoxymethylene)triphenylphosphorane (1.35 g).The reaction mixture was stirred for 2 hours at room temperature, andevaporated in vacuo.

2) To a mixture of above product and DMF (11 mL) was added(3R)-1-(cyclohexylmethyl)-3-pyrrolidinamine dihydrochloride (1.34 g) andK₂CO₃ (2.42 g). After stirring for 5 hours at 120° C., the reactionmixture was partitioned between ethyl acetate and H₂O. The organic layerwas washed with H₂O, dried over MgSO₄, filtered, and evaporated invacuo. The residue was purified by column chromatography on silica gelto give ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridazinyl)acrylate(499 mg).

¹H-NMR (300 MHz, CDCl₃) δ 0.81-0.96 (2H, m), 1.22-1.28 (4H, m), 1.34(3H, t, J=7 Hz), 1.37-1.49 (1H, m), 1.62-1.83 (5H, m), 2.19-2.45 (4H,m), 2.59-2.72 (2H, m), 2.82-2.93 (1H, m), 4.27 (2H, q, J=7 Hz),4.46-4.59 (1H, m), 5.29-5.35 (1H, m), 6.61 (1H, d, J=16 Hz), 6.62 (1H,d, J=9 Hz); 7.37 (1H, d, J=9 Hz), 7.79 (1H, d, J=16 Hz).

MS (ES+) m/z 359 (M+1).

Preparation 503

To a mixture of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylatedihydrochloride (250 mg), 4-(chloromethyl)-1,2-dimethylbenzene (89.0mg), and DMF (5.8 mL) was added K₂CO₃ (278 mg). After stirring for 2hours at room temperature, the reaction mixture was partitioned betweenethyl acetate and H₂O. The organic layer was washed with brine, driedover MgSO₄, filtered, and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(263 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 1.44 (9H, s), 1.98-2.27(8H, m), 2.53-3.00 (4H, m), 3.46-3.60 (2H, m), 4.28 (2H, q, J=7 Hz),4.84-4.96 (1H, m), 6.46 (1H, d, J=16 Hz), 6.93-7.06 (3H, m), 7.25-7.31(1H, m), 7.66 (1H, d, J=16 Hz), 7.75-7.82 (1H, m), 8.53 (1H, d, J=2 Hz).

MS (ES+) m/z 480 (M+1).

Preparation 504

To a solution of(2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acidhydrochloride (37 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine (19 mg),and 1-hydroxybenzotriazole (22 mg) in N,N-dimethylformamide (1 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25 mg) at 4° C. Themixture was warmed to ambient temperature and stirred for 8 hours. Thereaction mixture was added saturated NaHCO₃ (1 mL) and water (4 mL). Aresulting precipitate was collected by filtration, and washed with waterto give(2E)-3-(6-{([(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(43 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 1.48-1.74 (6H, m), 1.92-2.04 (1H, m),2.23-2.36 (1H, m), 3.09-3.64(5H, m), 3.89-4.00 (1H, m), 4.52-4.63 (1H,m), 4.88 (1H, brs), 6.23 (1H, d, J=16 Hz), 6.51-6.62 (4H, m), 7.12-7.19(2H, m), 7.32-7.41 (2H, m), 7.59-7.66 (1H, m), 8.20(1H, brs), 11.1 (1H,brs).

MS (ES+) m/z 409 (M+1).

Preparation 505

i) A mixture of 5-chloro-6-methyl-2-pyrazinecarboxylic acid (3.83 g) andthionyl chloride (8.09 mL) was stirred for 3 hours at reflux. Aftercooling, the reaction mixture was evaporated in vacuo.

ii) To a suspension of sodium borohydride (2.52 g) in H₂O (110 mL) wasadded above product in dioxane (10 mL) at 10° C. After stirring for 1hours at 10° C., the reaction mixture was extracted with ethyl acetate.The organic layer was dried over MgSO₄, filtered, and evaporated invacuo to give (5-chloro-6-methyl-2-pyrazinyl)methanol (2.36 g).

¹H-NMR (300 MHz, CDCl₃) δ 2.67 (3H, s), 2.86-2.95 (1H, m), 4.79 (2H, d,J=3 Hz), 8.25 (1H, s).

MS (ES+) m/z 159 (M+1).

Preparation 506

1) To a mixture of (5-chloro-6-methyl-2-pyrazinyl)methanol (2.35 g),ethyl acetate (50 mL), and dioxane (25 mL) was added manganese(IV) oxide(12.9 g). After stirring for 2 hours at reflux, a resulting precipitatewas filtered and the filtrate was evaporated in vacuo.

2) To a mixture of above product and THF (50 mL) was added(carbethoxymethylene)triphenylphosphorane (6.19 g). The reaction mixturewas stirred for 6 hours at room temperature, and evaporated in vacuo.The residue was purified by column chromatography on silica gel to giveethyl (2E)-3-(5-chloro-6-methyl-2-pyrazinyl)acrylate (863 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 2.68 (3H, s), 4.29 (2H,q, J=7 Hz), 7.01 (1H, d, J=16 Hz), 7.63 (1H, d, J=16 Hz), 8.26 (1H, s).

MS (ES+) m/z 227 (M+1).

Preparation 507

1) To a mixture of 6-chloro-3-pyridazinecarbaldehyde (300 mg) and THF (6mL) was added (carbethoxymethylene)triphenylphosphorane (805 mg). Thereaction mixture was stirred for 2 hours at room temperature, andevaporated in vacuo.

2) To a mixture of above product and DMF (10 mL) was added(3R)-1-benzyl-3-pyrrolidinamine (556 mg) and Et₃N (0.880 mL). Afterstirring for 5-hours at 100° C., the reaction mixture was partitionedbetween ethyl acetate and H₂O. The organic layer was washed with brine,dried over MgSO₄, filtered, and evaporated in vacuo. The residue waspurified by column chromatography on silica gel to give ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridazinyl)acrylate(237 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.60-1.79 (1H, m),2.25-2.94 (5H, m), 3.63-3.66 (2H, m), 4.27 (2H, q, J=7 Hz), 4.48-4.60(1H, m), 5.17-5.23 (1H, m), 6.59 (1H, d, J=9 Hz), 6.61 (1H, d, J=16 Hz),7.25-7.38 (6H, m), 7.78 (1H, d, J=16 Hz).

MS (ES+) m/z 353 (M+1).

Preparation 508

To a mixture of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylatedihydrochloride (500 mg), (2-bromoethoxy)benzene (347 mg), and DMF (5mL) was added Na₂CO₃ (488 mg). After stirring for 3 hours at 100° C.,the reaction mixture was partitioned between ethyl acetate and H₂O. Theorganic layer was washed with H₂O, dried over MgSO₄, filtered, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel to give ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(516 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 1.46 (9H, s), 1.98-2.10(1H, m), 2.16-2.30 (1H, m), 2.63-2.73 (1H, m), 2.78-2.98 (4H, m),3.08-3.16 (1H, m), 4.00-4.16 (2H, m), 4.28 (2H, q, J=7 Hz), 4.87-4.98(1H, m), 6.44 (1H, d, J=16 Hz), 6.86-6.97 (3H, m), 7.24-7.34 (3H, m),7.63 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.51 (1H, d, J=2 Hz).

MS (ES+) m/z 482 (M+1).

The following compound was obtained in a similar manner to that ofPreparation 508.

Preparation 509

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7 Hz), 1.23-1.51 (2H, m), 1.35(3H, t, J=7 Hz), 1.46 (9H, s), 1.57-1.71 (2H, m), 2.08-2.20 (1H, m),2.33-2.48 (1H, m), 2.60-3.50 (6H, m), 4.28 (2H, q, J=7 Hz), 4.95-5.08(1H, m), 6.47 (1H, d, J=16 Hz), 7.33 (1H, d, J=0.8 Hz), 7.65 (1H, d,J=16 Hz), 7.81 (1H, dd, J=2, 8 Hz), 8.57 (1H, brs).

MS (ES+) m/z 418 (M+1).

Preparation 510

1) To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-isobutyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(464 mg) in dioxane (11 mL) was added 1N sodium hydroxide (3.30 mL).After stirring at 60° C. for 2 hours, the reaction mixture was added H₂O(55 mL) and acidified with 1N hydrochloric acid (to pH 4). A resultingmixture was evaporated in vacuo

2) To a mixture of above product,O-tetrahydro-2H-pyran-2-ylhydroxylamine (195 mg), and1-hydroxybenzotriazole (225 mg) in N,N-dimethylformamide (6 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (259 mg) at 4° C.The mixture was warmed to ambient temperature and stirred for 8 hours.The reaction mixture was added saturated NaHCO₃ (6 mL) and water (24mL), and extracted with ethyl acetate. The organic layer was dried overMgSO₄, filtered, and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel to give(2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-isobutyl-3-pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 0.71-0.79 (6H, m), 1.36 (9H, s), 1.48-1.76(7H, m), 1.86-2.14 (4H, m), 2.35-2.59 (3H, m), 2.69-2.76 (1H, m),3.49-3.58 (1H, m), 3.90-4.03 (1H, m), 4.67-4.78 (1H, m), 4.92 (1H, brs),6.58 (1H, d, J=16 Hz), 7.34 (1H, d, J=8 Hz), 7.52 (1H, d, J=16 Hz), 8.00(1H, d, J=8 Hz), 8.62 (1H, brs), 11.3 (1H, brs).

MS (ES+) m/z 489 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 510.

Preparation 511

(2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.08-1.29 (6H, m), 1.47-2.25 (13H, m),2.39-2.53 (2H, m), 2.68-2.84 (2H, m), 3.49-3.57 (1H, m), 3.90-4.01 (1H,m), 4.22-4.33 (1H, m), 4.89 (1H, brs), 6.60 (1H, d, J=16 Hz), 7.38 (1H,d, J=16 Hz), 7.71-7.76 (1H, m), 7.97 (1H, brs), 8.11 (1H, brs), 11.2(1H, brs).

MS (ES+) m/z 416 (M+1).

Preparation 512

(2E)-3-(2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.47-1.79 (7H, m), 2.08-2.21 (1H, m),2.30-2.37 (1H, m), 2.44-2.63 (2H, m), 2.78-2.84 (1H, m), 3.47-3.61 (3H,m), 3.88-3.99 (1H, m), 4.27-4.37 (1H, m), 4.88 (1H, brs), 6.34 (1H, d,J=16 Hz), 7.20-7.34 (5H, m), 7.74-7.82 (1H, m), 8.51 (2H, s), 11.1 (1H,brs).

MS (ES+) m/z 424 (M+1′).

Preparation 513

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.52-1.96 (7H, m), 2.34-2.52 (2H, m),2.62-2.93 (3H, m), 3.58-3.68 (3H, m), 3.95-4.07 (1H, m), 4.34-4.50 (1H,m), 4.97-5.03 (1H, m), 6.60 (1H, d, J=9 Hz), 7.23-7.35 (7H, m), 7.67(1H, d, J=16 Hz).

MS (ES+) m/z 424 (M+1).

Preparation 514

(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-6-methyl-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.48-1.71 (6H, m), 1.79-1.92 (1H, m),2.06-2.68 (7H, m), 2.81-2.93 (1H, m), 3.48-3.63 (3H, m), 3.88-3.99 (1H,m), 4.36-4.48 (1H, m), 4.90 (1H, brs), 6.63 (1H, d, J=16 Hz), 6.81 (1H,d, J=7 Hz), 7.20-7.39 (6H, m), 8.00(1H, s), 11.2 (1H, brs).

MS (ES+) m/z 438 (M+1).

Preparation 515

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 0.76-0.92 (2H, m), 1.08-1.27 (4H, m),1.32-1.81 (12H, m), 2.15-2.29 (3H, m), 2.34-2.45 (2H, m), 2.56-2.66 (1H,m), 2.73-2.81 (1H, m), 3.49-3.58 (1H, m), 3.91-4.03 (1H, m), 4.35-4.48(1H, m), 4.92 (1H, brs), 6.62 (1H, d, J=16 Hz), 6.83 (1H, d, J=9 Hz),7.33-7.55 (3H, m), 11.3 (1H, brs).

MS (ES+) m/z 430 (M+1).

Preparation 516

To a solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(308 mg) in dioxane (7.4 mL) was added 1N sodium hydroxide (2.21 mL).After stirring at 60° C. for 2 hours, the reaction mixture was added H₂O(37 mL) and acidified with 1N hydrochloric acid (to pH 1). A resultingmixture was extracted with CHCl₃, and the organic layer was dried overMgSO₄, filtered, and evaporated in vacuo to give(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid dihydrochloride (214 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 0.88 (3H, t, J=7 Hz), 1.23-1.37 (2H, m),1.40 (9H, s), 1.52-1.65 (2H, m), 1.91-3.85 (9H, m), 6.65 (1H, d, J=16Hz), 7.42 (1H, d, J=8 Hz), 7.62 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2, 8Hz), 8.70 (1H, d, J=2 Hz).

MS (ES+) m/z 390 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 516.

Preparation 517

(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid dihydrochloride

¹H-NMR (300 MHz, CDCl₃) δ 1.45 (9H, s), 2.23-2.89 (8H, m), 3.37-4.46(6H, m), 5.10-5.24 (1H, m), 6.39 (1H, dd, J=2, 16 Hz), 7.16-7.40 (4H,m), 7.55 (1H, dd, J=2, 16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.35-8.43 (1H,m).

MS (ES+) m/z 452 (M+1).

Preparation 518

(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.8.0-0.92 (6H, m), 1.15-5.22 (14H, m), 1.42(9H; s), 6.68 (1H, d, J=16 Hz), 7.42-7.51 (1H, m), 7.61-7.70 (1H, m),8.20-8.28 (1H, m), 8.67-8.75 (1H, m).

MS (ES+) m/z 418 (M+1).

Preparation 519

(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.40 (9H, s), 1.87-5.20 (11H, m), 6.63 (1H,d, J=16 Hz), 6.94-7.02 (3H, m), 7.28-7.35 (2H, m), 7.40-7.48 (1H, m),7.60 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2, 8 Hz), 8.67 (1H, d, J=2 Hz).

MS (ES+) m/z 454 (M+1).

Preparation 520

To a mixture of(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid dihydrochloride (303 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine(109 mg.), and 1-hydroxybenzotriazole (125 mg) in N,N-dimethylformamide(3.1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (144mg) at 4° C. The mixture was warmed to ambient temperature and stirredfor 8 hours. The reaction mixture was added saturated NaHCO₃ (3 mL) andwater (12 mL), and extracted with ethyl acetate. The organic layer waswashed with H₂O and brine, dried over MgSO₄, filtered, and evaporated invacuo. The residue was purified by column chromatography on silica gelto give(2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(135 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 0.74 (6H, t, J=7 Hz), 1.09-1.25 (5H, m),1.36 (9H, s), 1.49-1.75 (6H, m), 1.88-2.19 (4H, m), 2.36-2.71 (4H, m),3.49-3.58 (1H, m), 3.90-4.02 (1H, m), 4.67-4.78 (1H, m), 4.92 (1H, brs),6.58 (1H, d, J=16 Hz), 7.33 (1H, d, J=8 Hz), 7.53 (1H, d, J=16 Hz), 8.00(1H, d, J=8 Hz), 8.63 (1H, brs).

MS (ES+) m/z 517 (M+1).

The following compounds were obtained in a similar manner to that ofPreparation 520.

Preparation 521

(2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.35 (9H, s), 1.50-1.77 (6H, m), 1.88-2.23(8H, m), 2.42-3.59 (7H, m), 3.91-4.03 (1H, m), 4.68-4.77 (1H, m),4.91-4.95 (1H, m), 6.59 (1H, d, J=16 Hz), 6.85 (1H, d, J=8 Hz), 6.93(1H, s), 7.00 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.54 (1H, d, J=16Hz), 7.97-8.03 (1H, m), 8.61 (1H, brs), 11.3 (1H, brs).

MS (ES+) m/z 551 (M+1).

Preparation 522

(2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-butyl-3-pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7 Hz), 1.23-3.45 (12H, m), 1.46(9H, s), 3.64-3.72 (1H, m), 3.93-4.04 (1H, m), 4.89-5.06 (2H, m),6.30-7.34 (2H, m), 7.68 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.56(1H, brs).

MS (ES+) m/z 489 (M+1).

Preparation 523

(2E)-3-(5-[(tert-butoxycarbonyl){(3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.45 (9H, s), 1.54-1.90 (6H, m), 1.98-2.10(1H, m), 2.16-2.31 (1H, m), 2.65-2.98 (5H, m), 3.07-3.19 (1H, m),3.63-3.74 (1H, m), 3.93-4.07 (3H, m), 4.86-5.07 (2H, m), 6.86-6.98 (3H,m), 7.24-7.34 (4H, m), 7.62-7.79 (2H, m), 8.53 (1H, brs).

MS (ES+) m/z 553 (M+1).

The following compound was obtained in a similar manner to that ofPreparation 309.

Preparation 524

ethyl5-chloro-6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 0.79-0.98 (2H, m), 1.07-1.31 (4H, m), 1.36(3H, t, J=7.1 Hz), 1.40-1.88 (9H, m), 2.01-2.24 (3H, m), 2.30-2.43 (1H,m), 2.58-2.76 (2H, m), 4.24-4.39 (3H, m), 6.37 (1H, br peak), 8.00 (1H,d, J=2.0 Hz), 8.66 (1H, d, J=2.0 Hz);

MS (ES+) m/z 380.

The following compound was obtained in a similar manner to that ofPreparation 3.

Preparation 525

ethyl (2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]acrylate

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.51-1.71 (6H, m), 1.92-1.99(2H, m), 4.16 (2H, q J=7.08 Hz), 4.32-4.43 (1H, m), 6.47 (1H, d J=15.84Hz), 6.65 (1H, d J=7.24 Hz), 7.51 (1H, d J=15.84 Hz), 8.08 (1H, d J=1.96Hz), 8.28 (1H, d J=1.96 Hz).

The following compound was obtained in a similar manner to that ofPreparation 426.

Preparation 526

ethyl(2E)-3-{6-[(tert-butoxycarbonyl){(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}amino]-3-pyridinyl}acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.91-1.02, (6H, m), 1.35 (3H, t, J=7.3 Hz),1.44 (9H, s), 1.50-1.72 (13H, m), 1.85-2.01 (3H, m), 2.07-2.33 (1H, m),2.44-2.59 (2H, m), 2.61-2.74 (1H, m), 2.76-2.89 (1H, m), 2.96-3.10 (2H,m), 4.28 (2H, q, J=7.3 Hz), 4.76-4.91 (1H, m), 6.46 (1H, d, J=16.1 Hz),7.28 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.8,2.6 Hz), 8.56 (1H, d, J=2.6 Hz);

MS (ES+) m/z 498(M+1).

The following compounds were obtained in a similar manner to that ofPreparation 405, Preparation 414.

Preparation 527

tert-butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl){(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 0.90 (3H, s), 0.92 (3H, s), 1.21-2.20 (7H,m), 1.36 (9H, s), 2.35-2.78 (4H, m), 2.95 (2H, br.s), 3.48-3.61 (1H, m),3.89-4.04 (1H, m), 4.62-4.80 (1H, m), 4.92 (1H, br.s), 6.58 (1H, d,J=16.5 Hz), 7.33 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=16.5 Hz), 7.99 (1H,br.d, J=8.4 Hz), 8.62 (1H, br.s);

MS (ES+) m/z 569(M+1).

Preparation 528

(2E)-3-(5-{[(3R)-1-(phenylacetyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.21-2.01 (10H, m), 2.66-2.78 (0.6H, m),3.01-4.03 (8H, m), 4.24-4.34 (0.4H, m), 4.90 (1H, br.s), 6.56-6.69 (1H,m), 7.11-7.68 (6H, m), 8.13 (0.4H, s), 8.18 (0.6H, s).

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 529

ethyl(2E)-3-(5-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.0 Hz), 1.63-1.77 (1H, m),2.31-2.46 (2H, m), 2.35 (3H, s), 2.62-2.75 (2H, m), 2.85-2.95 (1H, m),3.60 (2H, br.s), 4.25 (2H, q, J=7.0 Hz), 4.39-4.54 (1H, m), 5.23 (1H,br.d, J=8.1 Hz), 6.67 (1H, d, J=15.8 Hz), 7.04-7.15 (3H, m), 7.18-7.25(1H, m), 7.57 (1H, d, J=15.8 Hz), 7.87 (1H, br.s), 8.05 (1H, br.s);

MS (ES+) m/z 367(M+1).

The following compound was obtained in a similar manner to that ofPreparation 405, Preparation 414.

Preparation 530

(2E)-3-(5-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.44-1.77 (7H, m), 2.14-2.33 (1H, m), 2.28(3H, s), 2.34-2.50 (2H, m), 2.58-2.70 (1H, m), 2.71-2.80 (1H, m),3.47-3.57 (1H, m), 3.54 (2H, s), 3.87-4.03 (1H, m), 4.23-4.37 (1H, m),4.89 (1H, br.s), 6.59 (1H, d, J=15.0 Hz), 7.01-7.14 (3H, m), 7.15-7.23(1H, m), 7.37 (1H, d, J=15.0 Hz), 7.77 (1H, br.d), 7.97 (1H, br.s), 8.09(1H, br.s); MS (ES+) m/z 438(M+1).

The following compound was obtained in a similar manner to that ofPreparation 506.

Preparation 531

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) 0.79-0.99 (2H, m), 1.09-1.39 (4H, m), 1.33 (3H,t, J=7.0 Hz), 1.39-1.90 (9H, m), 2.03-2.20 (3H, m), 2.32-2.43 (1H, m),2.55-2.76 (2H, m), 4.22-4.33 (1H, m), 4.24 (2H, q, J=7.0 Hz), 6.19 (1H,d, J=15.8 Hz), 7.53 (1H, d, J=15.8 Hz), 7.66 (1H, d, J=1.8 Hz), 8.10(1H, d, J=1.8 Hz); MS (ES+) m/z 406(M+1).

The following compound was obtained in a similar manner to that ofPreparation 426.

Preparation 532

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3,3,5,5-tetramethylcyclohexyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (6H, br.s), 1.01 (6H, br.s), 1.36 (3H, t,J=7.0 Hz), 1.47 (9H, s), 1.57-1.75 (6H, m), 1.90-2.26 (2H, m), 2.32-2.97(4H, m), 3.17-3.30 (1H, m), 4.29 (2H, q, J=7.0 Hz), 4.77-4.94 (1H, m),6.47 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=16.1Hz), 7.82 (1H, dd, J=8.4, 2.6 Hz), 8.56 (1H, d, J=2.6 Hz);

MS (ES+) m/z 550(M+1).

The following compound was obtained in a similar manner to that ofPreparation 405, Preparation 414.

Preparation 533

tert-butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)[(3R)-1-(3,3,5,5-tetramethylcyclohexyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 0.86 (6H, s), 0.95 (6H, s), 1.12-1.77 (12H,m), 1.37 (9H, s), 1.78-2.08 (2H, m), 2.23-2.54 (2H, m), 2.54-2.77 (2H,m), 2.88-3.01 (1H, m), 3.49-3.60 (1H, m), 3.87-4.06 (1H, m), 4.57-4.72(1H, m), 4.89-4.96 (1H, m), 6.58 (1H, d, J=15.8 Hz), 7.34 (1H, d, J=8.4Hz), 7.52 (1H, d, J=15.8 Hz), 7.97-8.05 (1H, m), 8.60-8.66 (1H, m).

The following compounds were obtained in a similar manner to that ofPreparation 426.

Preparation 534

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.74-0.90 (2H, m), 0.98 (6H, s), 1.08 (6H, s),1.27 (3H, t, J=7.3 Hz), 1.37 (9H, s), 1.54-1.68 (4H, m), 1.78-1.93 (1H,m), 1.93-2.09 (1H, m), 2.34-2.69 (4H, m), 2.87-2.98 (1H, m), 4.21 (2H,q, J=7.3 Hz), 4.58-4.73 (1H, m), 6.76 (1H, d, J=16.1 Hz), 7.35 (1H, d,J=8.8 Hz), 7.69 (1H, d, J=16.1 Hz), 8.19 (1H, dd, J=8.8, 2.6 Hz), 8.73(1H, d, J=2.6 Hz);

MS (ES+) m/z 501(M+1).

Preparation 535

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7.3 Hz), 1.40-1.59 (2H, m),1.46 (9H, s), 1.72-1.82 (2H, m), 1.96-2.09 (1H, m), 2.11-2.35 (2H, m),2.50-2.63 (1H, m), 2.69 (1H, t, J=8.4 Hz), 2.76-2.88 (1H, m), 3.15 (1H,t, J=8.4 Hz), 3.32-3.44 (2H, m), 3.90-4.00 (2H, m), 4.28 (2H, q, J=7.3Hz), 4.81-4.97 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz),7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, diJ=2.6 Hz);

MS (ES+) m/z 446(M+1).

The following compound was obtained in a similar manner to that ofExample 129.

Preparation 536

(3R) 1-(cyclohexylmethyl)-3-piperidinamine dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.83-2.13 (15H, m), 2.69-3.95 (7H, m),8.42-8.66 (2H, m).

The following compound was obtained in a similar manner to that ofPreparation 405, Preparation 414.

Preparation 537

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 0.72-0.94 (2H, m), 1.01-1.31 (4H, m),1.37-1.82 (15H, m), 2.03-2.61 (6H, m), 3.46-3.59 (1H, m), 4.11-4.25 (1H,m), 4.89 (1H, br.s), 6.26-6.46 (2H, m), 7.36 (1H, d, J=15.8 Hz), 7.87(1H, br.s), 8.18-8.26 (1H, m); MS (ES+) m/z 477(M+1).

Preparation 538

A mixture of tert-butyl(3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(0.98 g) and 4N hydrogen chloride in dioxane solution (5 ml) in EtOH (10ml) was stirred at ambient temperature for 4 hours. The reaction mixturewas evaporated in vacuo and the residue was triturated with hexane wascollected by filtration to give ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino)-3-pyridinyl}acrylatedihydrochloride (0.9 g).ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.99-2.12 (2H, m), 3.19-3.45(3H, m), 3.56-3.65 (1H, m), 4.16 (2H, q J=7.08 Hz), 4.52-4.57 (1H, m),6.52 (1H, d J=15.94 Hz), 6.95 (1H, d J=6.52 Hz), 7.53 (1H, d J=15.94Hz), 8.13 (1H, d J=1.90 Hz), 8.31 (1H, d J=1.90 Hz).

The following compound was obtained in a similar manner to that ofPreparation 538.

Preparation 539

ethyl (2E)-3-{6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.06 Hz), 2.04-2.05 (1H, m), 2.29-2.34(1H, m), 3.24-3.29 (2H, m), 3.40-3.43 (1H, m), 3.45-3.52 (1H, m), 4.18(2H, q J=7.06 Hz), 4.66 (1H, br.s), 6.59 (1H, d J=16.00 Hz), 7.11 (1H, dJ=9.12 Hz), 7.65 (1H, d J=16.00 Hz), 8.27-8.32 (2H, m), 9.56 (1H, br.s),9.69 (1H, br, s).

Preparation 540

A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate(6.0 g) and 1-benzyl-3-aminopyrrolidine (5.78 g) in dioxane (10 ml) wasstirred at 130° C. for 15 hours under atmospheric pressure of nitrogen.The reaction mixture was poured into a mixture of AcOEt and H₂O and theorganic layer was washed with brine and dried over MgSO₄. The solventwas evaporated in vacuo and the residue was chromatographed on allunimaeluting with AcOEt-n-hexane (6:4). The eluted fractions containing thedesired product were collected and evaporated in vacuo to give benzyl2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate(3.06 g).

¹H-NMR (DMSO-d6): δ 1.71-1.81 (1H, m), 2.09-2.17 (1H, m), 2.47 (3H, s),2.35-2.60 (3H, m), 2.79-2.81 (1H, m), 3.56 (2H, s), 4.39 (1H, m), 5.27(2H, s), 7.22-7.47 (10H, m), 8.11-8.16 (H, m), 8.70 & 8.75 (total 1H,each s).

Preparation 541

A solution of benzyl 4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate(3.27 g), 1-benzyl-3-aminopyrrolidine (2.98 g) andN,N-diisopropylethylamine (1.75 g) in dioxane (15 ml) was stirred at130° C. for 11 hours under atmospheric pressure of nitrogen. Thereaction mixture was poured into a mixture of AcOEt and H₂O and theorganic layer was washed with brine and dried over MgSO₄. The solventwas evaporated in vacuo and the residue was chromatographed on alluminaeluting with AcOEt-n-hexane (5:5). The eluted fractions containing thedesired product were collected and evaporated in vacuo to give benzyl2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate (3.9g).

¹H-NMR (DMSO-d6): δ 1.71-1.81 (1H, m), 2.09-2.17 (1H, m), 2.47 (3H, s),2.35-2.60 (3H, m), 2.79-2.81 (1H, m), 3.56 (2H, s), 4.39 (1H, m), 5.27(2H, s), 7.22-7.47 (10H, m), 8.11-8.16 (1H, m), 8.70 & 8.75 (total 1H,each s).

The following compounds were obtained in a similar manner to that ofPreparation 541.

Preparation 542

benzyl2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinecarboxylate

¹H-NMR (DMSO-d6): δ 1.45-1.62 (2H, m), 1.78-1.83 (2H, m), 1.94-2.06 (2H,s), 2.52 (3H, s), 2.76-2.82 (2H, m), 3.36 (2H, s)_(m 3.78)-3.81 (1H, m),5.27 (2H, s), 7.23-7.44 (10H, m), 7.91-8.00 (1H, m), 8.68 & 8.77 (total1H, each s).

Preparation 543

benzyl4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinecarboxylate

¹H-NMR (DMSO-d6): δ 1.73-1.76 (1H, m), 2.13-2.60 (4H m), 2.27 (3H, s),2.45 (3H, s), 2.74-2.89 (1H, m), 3.51 (2H, s), 4.37 (1H, m), 5.26 (2H,s), 7.08-7.20 (5H, m), 7.30-7.48 (4H, m), 8.10-8.15 (1H, m), 8.69 & 8.75(total 1H, each s).

Preparation 544

benzyl2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinecarboxylate

¹H-NMR (DMSO-d6): δ 0.77-0.86 (2H, m), 1.12-1.32 (5H, m), 1.61-1.76 (5H,m), 2.00-2.56 (6H, m), 2.43 (3H, s), 2.74-2.78 (1H, m), 4.37-4.51 (1H,m), 5.27 (2H, s), 7.22-7.70 (5H, m), 8.65-8.69 (1H, m), 8.69 & 8.77(total 1H, each s).

Preparation 545

A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate(3.6 g) and m-chloroperbenzoic acid (P=75%) (2.72 g) in AcOEt (30 ml)was stirred at ambient temperature for 2 hours. The reaction mixture waspoured into a mixture of AcOEt and H₂O and the organic layer was washedwith saturated NaHCO₃ solution, brine and dried over MgSO₄. The solventwas evaporated in vacuo to give benzyl4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate (3.2 g)

¹H-NMR (DMSO-d6): δ 2.81 (3H, s), 2.90 (3H, s), 5.42 (2H, s) 7.23-7.55(5H, m), 9.27 (1H, s).

Preparation 546

A mixture of{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}methanol(1.75 g) and MnO₂ (5.1 g) in AcOEt (30 ml) was refluxed under stirringfor 1.5 hours. After removal of the insoluble material, and the solventwas evaporated in vacuo to give2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarbaldehyde(1.58 g).

¹H-NMR (DMSO-d6): δ 1.72-1.78 (1H, m), 2.15-2.19 (1H, m), 2.36-2.61 (3H,m), 2.48 (3H, s), 2.80-2.88 (1H, m), 3.35 (2H, s), 4.39-4.47 (1H, m),7.18-7.32 (5H, m), 8.34-8.43 (1H, m), 8.58 & 8.62 (total 1H, each s),9.81 & 9.84 (total 1H, each s).

The following compounds were obtained in a similar manner to that ofPreparation 546.

Preparation 547

2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinecarbaldehyde

¹H-NMR (DMSO-d6): δ 1.44-1.63 (2H, m), 1.78-1.84 (2H, m), 1.96-2.07 (2H,m), 2.49 (3H, s), 2.77-2.83 (2H, m), 3.45 (2H, s), 3.81-3.87 (1H, m),7.19-7.37 (5H, m), 8.14-8.26 (1H, m), 8.18 & 8.26 (total 1H, each s),9.81 & 9.84 (total 1H, each s).

Preparation 548

4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinecarbaldehyde

¹H-NMR (DMSO-d6): δ 1.74-1.77 (1H, m), 2.14-2.60 (4H, m), 2.27 (3H, s),2.46 (3H, s), 2.77-2.86 (1H, m), 3.52 (2H, s), 4.41-4.48 (1H, m), 7.10(2H, d J=8.02 Hz), 7.19 (2H, d J=8.02 Hz), 8.32-8.42 (1H, m), 8.58 &8.61 (total 1H, each s), 9.81 & 8.93 (total 1H, each s).

Preparation 549

2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinecarbaldehyde

¹H-NMR (DMSO-d6): 0.78-0.84 (2H, m), 1.13-1.73 (10H, m), 2.00-2.57 (6H,m), 2.47 (3H, s), 2.79-2.82 (1H, m), 4.41-4.51 (1H, m), 8.28-8.34 (1H,m), 8.64 & 8.73 (total 1H, each s), 9.86 & 9.90 (total 1H, each s).

Preparation 550

A solution of diethylphosphonoacetcacid ethyl ester (1.79 g) in THF (5ml) was added dropwise to a mixture of 60% sodium hydride in oil (341mg) in THF (60 mL) with stirring at 10-20° C. under atmospheric pressureof nitrogen, and the reaction mixture was stirred at ambient temperaturefor 30 minutes. A solution of2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarbaldehyde(1.58 g) in THF (10 ml) solution was added the above mixture andresultant mixture was stirred at ambient temperature for 1.5 hours. Thereaction mixture was poured into a mixture of AcOEt-H₂O and the organiclayer was washed with brine and dried over MgSO₄. The solvent wasevaporated in vacuo and the residue was chromatographed on silicageleluting with AcOEt-MeOH (9:1). The eluted fractions containing thedesired product were collected and evaporated in vacuo to give ethyl(2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate(1.7 g).

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.63-1.82 (1H, m), 2.04-2.30(1H, m), 2.34 (3H, s), 2.38-2.57 (3H, m), 2.79-2.84 (1H, m), 3.56 (2H,s), 4.18 (2H, q J=7.06 Hz), 4.35 (1H, m), 6.40 (1H, d J=15.94 Hz),7.18-7.32 (5H, m), 7.63 (1H, d J=15.94 Hz), 7.78-7.80 (1H, m), 8.63 (1H,s).

The following compounds were obtained in a similar manner to that ofPreparation 550.

Preparation 551

ethyl(2E)-3-{2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate

¹H-NMR (DMSO-d6): 1.24 (3H, t J=7.06 Hz), 1.47-1.54 (2H, m), 1.78-1.83(2H, m), 1.95-2.06 (2H, m), 2.37 (3H, s), 2.76-2.82 (2H, m), 3.45 (2H,s), 3.80 (1H, m), 4.18 (2H, q J=7.06 Hz), 6.39 (1H, d J=15.94 Hz),7.19-7.36 (6H, m), 7.63 (1H, d J=15.94 Hz), 8.64 (1H, s).

Preparation 552

ethyl(2E)-3-(4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.67-1.80 (1H, m), 2.02-2.49(2H, m), 2.27 (3H, s), 2.45 (3H, s), 2.49-2.55 (2H, m), 2.77-2.81 (1H,m), 3.51 (2H, s), 4.17 (2H, q J=7.06 Hz), 4.35 (1H, m), 6.39 (1H, dJ=15.96 Hz), 7.10 (2H, d J=8.02 Hz), 7.18 (2H, d J=8.02 Hz), 7.63 (1H, dJ=15.96 Hz), 7.76-7.79 (1H, m), 8.63 (1H, s).

Preparation 553

ethyl(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinyl)acrylate

¹H-NMR (DMSO-d6): δ 0.77-0.83 (2H, m), 1.25 (3H, t J=7.08 Hz), 1.15-1.17(4H, m), 1.23-1.26 (1H, m), 1.63-1.74 (6H, m), 2.15-2.19 (3H, m), 2.37(3H, s), 2.19-2.52 (2H, m), 2.76-2.78 (1H, m), 4.17 (2H, q J=7.08 Hz),4.33-4.34 (1H, m), 6.40 (1H, d J=15.96 Hz), 7.63 (1H, d J=15.96 Hz),7.74 (1H, m), 8.65 (1H, s).

Preparation 554

Lithium aluminium hydride (646 mg) was portionwise added to a solutionof benzyl2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate(4.56 g) in THF (60 ml) with stirring at 5-15° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at 5-20° C.for 2 hours. The reaction mixture was cooled at 5° C. and H₂O (0.7 ml),15% NaOH solution (0.7 ml) and H₂O (2.1 ml) was added and the resultantmixture was stirred at ambient temperature for 30 minutes. The reactionmixture was filtrated and the filtrate was dried over MgSO₄. The solventwas evaporated in vacuo and the residue was chromatographed on silicageleluting with AcOEt-MeOH (9:1). The eluted fractions containing thedesired product were collected and evaporated in vacuo to give(2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl)methanol (1.1g).

¹H-NMR (DMSO-d6): δ 1.69-1.72 (1H, m), 2.12-2.36 (2H, m), 2.29 (3H, s),2.47-2.59 (2H, m), 2.79-2.87 (1H, m), 3.52 (1H, d J=13.02 Hz), 3.59 (1H,d J=13.02 Hz), 4.29-4.32 (3H, m), 4.90 (1H, br.s), 7.07 (1H, d J=6.94Hz), 7.12-7.32 (5H, m), 8.04 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 554.

Preparation 555

{2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinyl}methanol

¹H-NMR (DMSO-d6): δ 1.37-1.56 (2H, m), 1.77-1.82 (2H, m), 1.96-2.06 (2H,m), 2.27 (3H, s), 2.74-2.80 (2H, m), 3.44 (2H, s), 3.66-3.71 (1H, m),4.30 (2H, d J=5.16 Hz), 4.85 (1H, t J=5.16 Hz), 6.85 (1H, d J=7.96 Hz),7.19-7.36 (5H, m), 8.02 (1H, s).

Preparation 556

(4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)methanol

¹H-NMR (DMSO-d6): δ 1.68-1.70 (1H, m), 1.91-2.33 (2H, m), 2.27 (3H, s),2.45 (3H, s), 2.45-2.58 (2H, m), 2.76-2.84 (1H, m), 3.47 (1H, d J=12.90Hz), 3.55 (1H, d J=12.90 Hz), 4.31 (2H, s), 3.98-7.04 (1H, m), 7.02-7.20(6H, m), 8.02 (1H, s).

Preparation 557

(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinyl)methanol

¹H-NMR (DMSO-d6): δ 0.78-0.89 (2H, m), 1.13-1.62 (5H, m), 1.69-1.99 (5H,m), 2.28 (3H, s), 2.00-2.28 (4H, m), 2.42-2.52 (2H, m), 2.73-2.81 (1H,m), 4.41-4.49 (1H, m), 4.49 (2H, s), 5.27 (1H, m), 6.91 (1H, d J=6.98Hz), 8.03 (1H, s).

Preparation 558

A solution of ethyl(2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate(750 mg) and 1N NaOH solution (4.1 ml) in MeOH (10 ml) and THF (10 ml)was stirred at 80-85° C. for 2 hours. The reaction mixture wasevaporated in vacuo and the residue was dissolved in a mixture was AcOEtand H₂O. The aqueous solution was adjusted to PH 5.4 with 5% HClsolution and resultant solution was evaporated in vacuo and the residuewas dissolved in a MeOH and THF. The solvent was evaporated in vacuo anddried to give(2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylicacid (693 mg).

¹H-NMR (DMSO-d6): δ 1.72-1.84 (1H, m), 2.13-2.30 (1H, m), 2.34 (3H, s),2.34-2.87 (4H, m), 3.57 (2H, s), 4.27-4.33 (1H, m), 6.29 (1H, d J=15.90Hz), 7.11-7.32 (6H, m), 7.41-7.62 (2H, m), 8.47 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 558.

Preparation 559

(2E)-3-{2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinyl}acrylicacid

¹H-NMR (DMSO-d6): δ 1.74-2.09 (4H, m), 2.38 (3H, s), 2.69 (2H, m),3.04-3.09 (2H, m), 3.95-4.11 (3H, m), 6.34 (1H, d J=15.96 Hz), 7.38-7.54(5H, m), 7.58 (1H, d J=15.96 Hz), 7.72 (1H, d J=7.20 Hz), 8.61 (1H, s).

Preparation 560

(2E)-3-(4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.73-1.82 (1H, m), 2.00-2.33 (2H, m), 2.27 (3H, s),2.45 (3H, s), 2.45-2.68 (2H, m), 2.77-2.85 (1H, m), 3.51-3.52 (2H, m),4.31-4.34 (1H, m), 6.26 (1H, d J=15.68 Hz), 7.08-7.36 (5H, m), 7.47 (1H,d J=6.90 Hz), 8.45 (1H, s).

Preparation 561

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 0.78-0.90 (2H, m), 1.13-1.63 (5H, m), 1.50-1.84 (6H,m), 2.00-2.53 (5H, m), 2.35 (3H, s), 2.75-2.80 (1H, m), 4.20 (1H, m),6.29 (1H, d J=15.86 Hz), 7.32 (1H, d J=15.86 Hz), 7.42-7.49 (1H, m),8.49 (1H, s).

Preparation 562

A mixture of A mixture of(2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylicacid (693 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (264 mg), HOBt(290 mg) and EDCI (334 mg) in DMF (20 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof AcOEt-H₂O and the organic layer was washed with brine and dried overMgSO₄. The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with AcOEt-MeOH (9:1). The elutedfractions containing the desired product were collected and evaporatedin vacuo to give(2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(200 mg).

¹H-NMR (DMSO-d6): δ 1.59-1.74 (7H, m), 1.99-2.59 (4H, m), 2.37 (3H, s),2.79-2.87 (1H, m), 3.56 (2H, s), 3.98-4.05 (1H, m), 4.34 (1H, m), 4.89(1H, s), 6.26 (1H, d J=15.98 Hz), 7.18-7.36 (5H, m), 7.46 (1H, d J=15.98Hz), 7.64-7.69 (1H, m), 8.42 (1H, s), 11.13 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 562.

Preparation 563

(2E)-3-{2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.42-1.83 (10H, m), 1.95-2.12 (2H, m), 2.36 (3H, s),2.73-2.82 (2H, m), 3.33 (2H, s), 3.27-3.45 (1H, m), 3.78-3.80 (1H, m),3.95 (1H, m), 4.88 (1H, s), 6.25 (1H, d J=15.50 Hz), 7.23-7.72 (6H, m),7.46 (1H, d J=15.50 Hz), 8.42 (1H, s), 11.13 (1H, s).

Preparation 564

(2E)-3-(4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.65-1.99 (7H, m), 2.09-2.36 (4H, m), 2.27 (3H, s),2.45 (3H, s), 2.76-2.84 (1H, m), 3.51-3.55 (3H, m), 3.98-7.02 (1H, m),7.32 (1H, m), 4.88 (1H, s), 6.26 (1H, d J=15.62 Hz), 7.10 (2H, d J=8.04Hz), 7.18 (2H, d J=8.04 Hz), 7.46 (1H, d J=15.62 Hz), 7.63 (1H, d J=6.52Hz), 8.41 (1H, s), 11.12 (1H, s).

Preparation 565

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): 0.79-0.84 (2H, m), 1.06-1.77 (15H, m), 2.09-2.52 (7H,m), 2.35 (3H, s), 3.54-3.56 (1H, m), 3.93-3.99 (1H, m), 4.32 (1H, m),4.89 (1H, s), 6.27 (1H, d J=15.52 Hz), 7.48 (1H, d J=15.52 Hz), 7.59(1H, d J=6.72 Hz), 8.43 (1H, s), 11.13 (1H, br.s).

Preparation 566

A mixture of ethyl 5,6-dichloronicotinate (5.0 g), tert-butyl(3R)-3-amino-1-pyrrolidinecarboxylate (5.08 g) and K₂CO₃ (4.71 g) in DMF(40 ml) was stirred at 100° C. for 12 hours under atmospheric pressureof nitrogen. The reaction mixture was poured into a mixture of AcOEt andH₂O and the organic layer was washed with brine and dried over MgSO₄.The solvent was evaporated in vacuo and the residue was chromatographedon silicagel eluting with n-Hexane-AcOEt (9:1). The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive ethyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-chloronicotinate(6.6 g).

¹H-NMR (DMSO-d6): δ 1.26 (3H, t J=7.06 Hz), 1.40 (9H, s), 1.96-2.13 (2H,m), 3.18-3.45 (3H, m), 3.58-3.66 (1H, m), 4.27 (2H, q J=7.06 Hz),4.58-4.62 (1H, m), 7.24 (1H, d J=6.64 Hz), 7.95 (1H, d J=1.96 Hz), 8.57(1H, d J=1.96 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 566.

Preparation 567

ethyl 6-[(4-tert-butylcyclohexyl)amino]-5-chloronicotinate

¹H-NMR (DMSO-d6): δ 0.85(9H, s), 0.94-2.05(9H, m), 1.29(3H, t, J=7.0Hz), 3.85-4.05 and 4.16-4.33(total 1H, each m), 1.18-4.33(2H, m), 6.03and 6.83(total 1H, each d, J=6.4 Hz), 7.90 and 7.97(total 1H, each d,J=2.0 Hz), 8.53 and 8.57(total 1H, each d, J=2.0 Hz).

Preparation 568

ethyl 5-chloro-6-(cyclopentylamino)nicotinate

¹H-NMR (DMSO-d6): δ 1.26 (3H, t J=7.06 Hz), 1.56-1.73 (6H, m), 1.93-2.00(2H, m), 4.26 (2H, q J=7.06 Hz), 4.37-4.48 (1H, m), 6.93 (1H, d J=7.34Hz), 7.91 (1H, d J=1.98 Hz), 8.54 (1H, d J=1.98 Hz).

Preparation 569

methyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}nicotinate

¹H-NMR (DMSO-d6): δ 1.40 (9H, s), 1.80-1.89 (1H, m), 2.10-2.16 (1H, m),3.11-3.16 (1H, m), 3.32-3.38 (2H, m), 3.42-3.56 (1H, m), 3.77 (3H, s),4.43 (1H, m), 6.54 (1H, d J=8.86 Hz), 7.65 (1H, d J=6.34 Hz), 7.83 (1H,dd J=2.24 Hz, 8.86 Hz), 8.59 (1H, d J=2.24 Hz).

Preparation 570

A solution of diisobutylaluminium hydride in hexane solution (0.93M)(138 ml) was added to dropwise a solution of ethyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-chloronicotinate(15.9 g) in THF (200 ml) with stirring at 0-15° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at 5-20° C.for 4 hours. The reaction mixture was cooled at 5° C. and MeOH (10 ml)was added and the reaction mixture was stirred at ambient temperaturefor 20 minutes. The potassium sodium tatarate tetrahydrate (36.4 g) wasadded to a above solution and the resultant mixture was stirred atambient temperature for 2 hours. The reaction mixture was filtrated andthe filtrate was dried over MgSO₄. The solvent was evaporated in vacuoand the residue was chromatographed on silicagel eluting withAcOEt-n-hexane (9:1). The eluted fractions containing the desiredproduct were collected and evaporated in vacuo to give tert-butyl(3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate(5.85 g).

¹H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.90-2.14 (2H, m), 3.11-3.46 (3H, m),3.56-3.65 (1H, m), 4.35 (2H, d J=5.56 Hz), 4.38-4.48 (1H, m), 5.09 (1H,t J=5.56 Hz), 6.38 (1H, d J=6.20 Hz), 7.56 (1H, d J=1.90 Hz), 7.95 (1H,d J=1.90 Hz).

Preparation 571

A mixture of tert-butyl(3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate(0.95 g) and MnO₂ (3.02 g) in AcOEt (30 ml) was refluxed under stirringfor 1.5 hours. After removal of the insoluble material, and the solventwas evaporated in vacuo to give tert-butyl(3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate(0.95 g).

¹H-NMR (DMSO-d6): δ 1.40 (9H, s), 1.99-2.15 (2H, m), 3.20-3.46 (3H, m);3.56-3.67 (1H, m), 4.64-4.72 (1H, m), 7.49 (1H, d J=6.70 Hz), 7.95 (1H,d J=1.90 Hz), 8.57 (1H, d J=1.90 Hz), 9.76 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 571.

Preparation 572

5-chloro-6-(cyclopentylamino)nicotinaldehyde

¹H-NMR (DMSO-d6): δ 1.53-1.73 (6H, m), 1.80-1.97 (2H, m), 4.40-4.57 (1H,m), 7.24 (1H, d J=7.32 Hz), 7.90 (1H, d J=1.88 Hz), 8.53 (1H, d J=1.88Hz), 9.72 (1H, s).

Preparation 573

6-[(4-tert-butylcyclohexyl)amino]-5-chloronicotinaldehyde

¹H-NMR (DMSO-d6): δ 0.98 (9H, s), 0.98-1.65 (6H, m), 1.61-1.93 (3H, m),4.39-4.10 & 4.29-4.30 (total 1H, m), 6.25 & 7.14 (total 1H, each dJ=6.40 Hz), 7.89 & 7.96 (total 1H, each d J=1.82 Hz), 8.52 & 8.57 (total1H, each d J=1.82 Hz), 9.71 & 9.75 (total 1H, each s).

Preparation 574

tert-butyl (3R)-3-[(5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate

¹H-NMR (DMSO-d6): δ 1.40 (9H, s), 1.82-1.88 (1H, m), 2.12-2.14 (1H, m),3.13-3.18 (1H, m), 3.33-3.44 (2H, m), 3.56-3.63 (1H, m), 4.48 (1H, m),6.61 (1H, d J=8.78 Hz), 7.56 (1H, dd J=2.18 Hz, 8.78 Hz), 8.53 (1H, dJ=2.18 Hz), 9.70 (1H, s).

Preparation 575

A solution of diethylphosphonoacetcacid ethyl ester (980 mg), in THF (5ml) was added dropwise to admixture of 60% sodium hydride in oil (187mg) in THF (30 mL) with stirring at 10-20° C. under atmospheric pressureof nitrogen, and the reaction mixture was stirred at ambient temperaturefor 30 minutes. A solution of tert-butyl(3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate(0.95 g) in THF (10 ml) solution was added the above mixture andresultant mixture was stirred at ambient temperature for 1.5 hours. Thereaction mixture was poured into a mixture of AcOEt-H₂O and the organiclayer was washed with brine and dried over MgSO₄. The solvent wasevaporated in vacuo and the residue was chromatographed on silicageleluting with AcOEt-n-hexane (6:4). The eluted fractions containing thedesired product were collected and evaporated in vacuo to givetert-butyl(3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(0.98 g)

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.10 Hz), 1.40 (9H, s), 1.90-2.12 (2H,m), 3.19-3.45 (3H, m), 3.56-3.65 (1H, m), 4.16 (2H, q J=7.10 Hz),4.57-4.60 (1H, m), 6.52 (1H, d J=15.96 Hz), 6.96 (1H, d J=6.50 Hz), 7.53(1H, d J=15.96 Hz), 8.13 (1H, d J=1.82 Hz), 8.31 (1H, d J=1.82 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 575.

Preparation 576

ethyl(2E)-3-{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}acrylate

¹H-NMR (DMSO-d6): δ 0.97 (9H, s), 1.01-2.00 (9H, m), 1.24 (3H, t J=7.06Hz), 3.96-4.02 (1H, m), 4.16 (2H, q J=7.06 Hz), 5.78 & 6.53 (total 1H,each d J=6.58 Hz), 6.46 & 6.50 (total 1H, each d J=15.98 Hz), 7.50 &7.52 (total 1H, each d J=15.98 Hz), 8.08 & 8.14 (total 1H, each d J=1.94Hz), 8.25 & 8.30 (total 1H, each d J=1.94 Hz), APCI-MS (m/z): 395(M+H)+.

Preparation 577

tert-butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.40 (9H, s), 1.80-1.86 (1H,m), 2.10-2.13 (1H, m), 3.05-3.16 (1H, m), 3.31-3.40 (2H, m), 3.53-3.58(1H, m), 4.13 (2H, q, J=7.06 Hz), 4.39 (1H, m), 6.35 (1H, d J=15.86 Hz),6.55 (1H, d J=8.84 Hz), 7.46 (1H, d J=6.78 Hz), 7.52 (1H, d J=15.86 Hz),7.83 (1H, dd J=2.02 Hz, 8.84 Hz), 8.25 (1H, d J=2.02 Hz).

Preparation 578

Lithium aluminium hydride (1.02 g) was added to a solution of methyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}nicotinate (5.76g) in THF (80 ml) with stirring at 5-15° C. under atmospheric pressureof nitrogen, and the reaction mixture was stirred at 5-20° C. for 3hours. The reaction mixture was cooled at 5° C. and H₂O (1 ml), 15% NaOHsolution (1 ml) and H₂O (3 ml) was added and the resultant mixture wasstirred at ambient temperature for 30 minutes. The reaction mixture wasfiltrated and the filtrate was dried over MgSO₄. The solvent wasevaporated in vacuo and the residue was chromatographed on silicageleluting with AcOEt-MeOH (9:1). The eluted fractions containing thedesired product were collected and evaporated in vacuo to givetert-butyl(3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate(1.82 g).

¹H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.76-1.99 (1H, m), 2.07-2.12 (1H, m),3.06-3.13 (1H, m), 3.29-3.41 (2H, m), 3.42-3.57 (1H, m), 4.29 (2H, dJ=5.52 Hz), 4.28-4.38 (1H, m), 4.91 (1H, t J=5.52 Hz), 6.47 (1H, dJ=8.50 Hz), 6.66 (1H, d J=5.80 Hz), 7.35 (1H, dd J=2.02 Hz, 8.50 Hz),7.90 (1H, d J=2.02 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 578.

Preparation 579

[5-chloro-6-(cyclopentylamino)-3-pyridinyl]methanol

¹H-NMR (DMSO-d6): δ 1.44-1.68 (6H, m), 1.87-1.99 (2H, m), 4.20-4.37 (1H,m), 4.32 (2H, d J=5.72 Hz), 5.04 (1H, t J=5.72 Hz), 5.90 (1H, d J=7.12Hz), 7.51 (1H, d J=1.94 Hz), 7.92 (1H, d J=1.94 Hz).

Preparation 580

{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}methanol

¹H-NMR (DMSO-d6): 0.97 (9H, s), 0.97-1.56 (6H, m), 1.73-1.99 (3H, m),3.78-3.82 (1H, m), 4.16-4.35 (2H, m), 5.01-5.10 (1H, m), 5.27 & 5.74(total 1H, each d J=5.88 Hz), 7.50 & 7.56 (total 1H, each d J=1.92 Hz),7.89 & 7.94 (total 1H, each d J=1.92 Hz).

Preparation 581

A solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (2.0 g) in H₂O (10 ml) was adjusted to pH 8.5 With 20%K₂CO₃ solution and extracted with CHCl₃. The extract was dried overMgSO₄, the solvent was evaporated in vacuo to give ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (1.47g).

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.99-2.09 (2H, m), 2.64-2.75(2H, m), 2.87-3.01 (2H, m), 4.16 (2H, q J=7.08 Hz), 4.44-4.47 (1H, m),6.49 (1H, d J=15.94 Hz), 6.72 (1H, d J=7.14 Hz), 7.52 (1H, d J=15.94Hz), 8.09 (1H, d J=1.96 Hz), 8.28 (1H, d J=1.96 Hz).

Preparation 582

A mixture of tert-butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(600 mg) and 1N NaOH solution (3.3 ml) in MeOH (10 ml) and THF (10 ml)was stirred at 70-75° C. for 2 hours. The reaction mixture wasevaporated in vacuo and the residue was dissolved in a mixture of AcOEtand H₂O. The aqueous solution was adjusted to PH4.5 and extracted withAcOEt and THF. The organic layer was washed with brine and dried overMgSO₄. The solvent was concentrated in vacuo and the precipitate wascollected by filtration to give(2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (0.45 g).

¹H-NMR (DMSO-d6): δ 1.41 (9H, s), 1.84-1.87 (1H, m), 2.11-2.14 (1H, m),3.10-3.19 (1H, m), 3.34-3.42 (2H, m), 3.55-3.58 (1H, m), 4.36-4.42 (1H,m), 6.29 (1H, d J=15.88 Hz), 6.62 (1H, d J=8.76 Hz), 7.48 (1H, d J=15.88Hz), 7.64 (1H, m), 7.85 (1H, dd J=2.16 Hz, 8.76 Hz), 8.23 (1H, d J=2.16Hz), 11.14 (1H, s).

Preparation 583

A mixture of(2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (450 mg), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (174 mg), HOBt(191 mg) and EDCI (220 mg) in DMF (20 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof AcOEt-H₂O and the organic layer was washed with brine and dried overMgSO₄. The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with AcOEt-MeOH (95:5). The elutedfractions containing the desired product were collected and evaporatedin vacuo to give tert-butyl(3R)-3-[(5-[(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl)-2-pyridinyl)amino]-1-pyrrolidinecarboxylate(450 mg).

¹H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.69-2.00 (7H, m), 2.00-2.12 (1H, m),3.09-3.15 (1H, m), 3.34-3.43 (3H, m), 3.50-3.55 (2H, m), 3.93-3.95 (1H,m), 4.37 (1H, m), 4.88 (1H, s), 6.24 (1H, d J=15.74 Hz), 6.55 (1H, dJ=8.76 Hz), 7.30 (1H, d J=8.12 Hz), 7.37 (1H, d J=15.74 Hz), 7.63 (1H, dJ=8.76 Hz), 8.17 (1H, s), 11.06 (1H, s).

Preparation 584

A solution of ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(330 mg) and 1N NaOH solution (1.5 ml) in MeOH (30 ml) was stirred at80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo andthe residue was dissolved in a mixture was AcOEt and H₂O. The aquoussolution was adjusted to PH 5.4 with 5% HCl solution and resultantsolution was evaporated in vacuo and the residue was dissolved in a MeOHand THF. The solvent was evaporated in vacuo and dried to give(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (306 mg).

¹H-NMR (DMSO-d6): δ 0.80-0.91 (2H, m), 1.14-1.62 (4H, m), 1.71-1.84 (7H,m), 2.13-2.62 (4H, m), 2.73-2.81 (1H, m), 4.39-4.45 (1H, m), 6.36 (1H, dJ=15.88 Hz), 6.45 (1H, d J=7.08 Hz), 7.26 (1H, d J=15.88 Hz), 7.94 ₁(1H,d J=1.76 Hz), 8.17 (1H, d J=1.76 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 584.

Preparation 585

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.62-1.81 (9H, m), 2.30-2.52 (5H, m), 2.75-2.79 (1H,m), 4.38-4.45 (1H, m), 6.29 (1H, d J=15.84 Hz), 6.30 (1H, d J=7.20 Hz),7.07 (1H, d J=15.84 Hz), 7.84 (1H, d J=1.84 Hz), 8.10 (1H, d J=1.84 Hz).

Preparation 586

(2E)-3-(5-chloro-6-{[(3R)-1-(3-methyl-2-buten-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.61 (3H, s), 1.68 (3H, s), 1.68-1.79 (1H, m),2.00-2.30 (1H, m), 2.42-2.82 (4H, m), 3.00 (2H, m), 4.44-4.49 (1H, m),5.20-5.27 (1H, m), 6.37 (1H, d J=15.88 Hz), 6.50 (1H, d J=6.98 Hz), 7.27(1H, d J=15.68 Hz), 7.96 (1H, d J=1.86 Hz), 8.18 (1H, d J=1.86 Hz).

Preparation 587

(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyridinylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): 1.80-1.87 (1H, m), 2.18-2.47 (1H, m), 2.47-2.57 (2H,m), 2.66-2.73 (1H, m), 2.85-2.90 (1H, m), 3.72 (2H, s), 4.48-4.51 (1H,m), 6.34 (1H, d J=15.90 Hz), 6.46 (1H, d J=6.94 Hz), 7.13-7.28 (2H, m),7.42-7.46 (1H, m), 7.72-7.76 (1H, m), 7.88 (1H, d J=1.80 Hz), 8.12 (1H,d J=1.80 Hz), 8.47-8.50 (1H, m).

Preparation 588

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 0.08-0.13 (2H, m), 0.40-0.49 (2H, m), 0.78-0.95 (1H,m), 1.70-1.90 (1H, m), 2.08-2.25 (1H, m), 2.31 (2H, d J=6.60 Hz),2.50-2.60 (2H, m), 2.73-2.90 (2H, m), 4.49-4.56 (1H, m), 6.38 (1H, dJ=15.90 Hz), 6.56 (1H, d J=7.06 Hz), 7.26 (1H, d J=15.90 Hz), 7.94 (1H,d J=1.84 Hz), 8.18 (1H, d J=1.84 Hz).

Preparation 589

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.16-1.22 (2H, m), 1.45-2.30 (14H, m), 2.52-2.67(1H, m), 2.79-2.84 (1H, m), 4.44-4.51 (1H, m), 6.39 (1H, d J=15.86 Hz),6.55 (1H, d J=7.08 Hz), 7.34 (1H, d J=15.86 Hz), 7.99 (1H, d J=1.82 Hz),8.20 (1H, d J=1.82 Hz).

Preparation 590

A solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (1.0 g), bromomethylcyclobutane (456 mg) andN,N-diisopropylethylamine (1.26 g) in DMF (30 ml) was stirred at 80-85°C. for 12 hours under atmospheric pressure of nitrogen. The reactionmixture was poured into a mixture of AcOEt and H₂O and the organic layerwas washed with brine and dried over MgSO₄. The solvent was evaporatedin vacuo and the residue was chromatographed on silicagel eluting withAcOEt-MeOH (95:5). The eluted fractions containing the desired productwere collected and evaporated in vacuo to give ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(356 mg).

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 1.70-2.09 (9H, m), 2.46-2.52(6H, m), 2.73-2.77 (1H, m), 4.16 (2H, q J=7.08 Hz), 4.43-4.50 (1H, m),6.49 (1H, d J=15.96 Hz), 6.67 (1H, d J=7.00 Hz), 7.52 (1H, d J=15.96Hz), 8.10 (1H, d J=1.92 Hz), 8.28 (1H, d J=1.92 Hz).

The following compound was obtained in a similar manner to that ofPreparation 590.

Preparation 591

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(3-methyl-2-buten-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 1.61 (3H, s), 1.68 (3H, s),1.78-1.81 (1H, m), 2.14-2.19 (1H, m), 2.43-2.52 (2H, m), 2.60-2.89 (2H,m), 3.02 (2H, d J=6.76 Hz), 3.39 (1H, m), 4.16 (2H, q J=7.08 Hz),4.44-4.51 (1H, m), 5.20-5.26 (1H, m), 6.49 (1H, d J=15.94 Hz), 6.69 (1H,d J=6.94 Hz), 7.52 (1H, d J=15.94 Hz), 8.10 (1H, d J=1.94 Hz), 8.28 (1H,d J=1.94 Hz).

Preparation 592

A mixture of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (0.73g), m-tolualdehyde (356 mg) and sodium triacetoxyborohydride (1.57 g) inCH₂Cl₂ (30 ml) was stirred at 25-30° C. for 15 hours. The 10% K₂CO₃solution (20 ml) was added to a reaction mixture and resultant mixturewas stirred at ambient temperature for 30 minutes and extracted withCH₂Cl₂ and washed with brine and dried over MgSO₄. The solvent wasevaporated in vacuo and the residue was chromatographed on silicageleluting with AcOEt-MeOH (97:3). The eluted fractions containing thedesired product were collected and evaporated in vacuo to give ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(820 mg).

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.86-1.99 (1H, m), 2.16-2.40(1H, m), 2.40 (3H, s), 2.42-2.53 (2H, m), 2.62-2.66 (1H, m), 2.77-2.85(1H, m), 3.54 (2H, s), 4.16 (2H, q J=7.06 Hz), 4.45-4.53 (1H, m), 6.49(1H, d J=15.96 Hz), 6.72 (1H, d J=6.92 Hz), 7.02-7.24)₄H, m), 7.51 (1H,d J=15.96 Hz), 8.10 (1H, d J=1.90 Hz), 8.20 (1H, d J=1.90 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 592.

Preparation 593

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 0.80-0.92 (2H, m), 1.12-1.34 (4H, m), 1.24 (3H, tJ=7.08 Hz), 1.63-1.78 (5H, m), 2.18-2.22 (2H, m), 2.37-2.52 (3H, m),2.76-2.80 (1H, m), 3.16-3.22 (2H, m), 4.16 (2H, q J=7.08 Hz), 4.48-4.51(1H, m), 6.49 (1H, d J=15.96 Hz), 6.95 (1H, d J=7.02 Hz), 7.52 (1H, dJ=15.96 Hz), 8.10 (1H, d J=1.90 Hz), 8.28 (1H, d J=1.90 Hz).

Preparation 594

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.85-1.92 (1H, m), 2.18-2.22(1H, m), 2.42-2.49 (2H, m), 2.61-2.68 (1H, m), 2.80-2.89 (1H, m), 3.62(2H, s), 4.16 (2H, q J=7.08 Hz), 5.31-5.36 (1H, m), 6.49 (1H, d J=15.92Hz), 6.74 (1H, d J=6.92 Hz), 7.01-7.17 (3H, m), 7.30-7.41 (1H, m), 7.52(1H, d J=15.92 Hz), 8.10 (1H, d J=1.84 Hz), 8.27 (1H, d J=1.84 Hz).

Preparation 595

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyridinylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.84-1.91 (1H, m), 2.10-2.23(1H, m), 2.49-2.58 (2H, m), 2.70-2.74 (1H, m), 2.86-2.95 (1H, m), 3.73(2H, s), 4.16 (2H, q J=7.06 Hz), 4.52-4.59 (1H, m), 6.49 (1H, d J=15.90Hz), 6.75 (1H, d J=6.92 Hz), 7.22-7.28 (1H, m), 7.42-7.48 (1H, m), 7.52(1H, d J=15.90 Hz), 7.72-7.76 (1H, m), 8.10 (1H, d J=1.92 Hz), 8.27 (1H,d J=1.92 Hz), 8.47-8.50 (1H, m).

Preparation 596

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 0.34-0.11 (2H, m), 0.39-0.48 (2H, m), 0.70-0.92 (1H,m), 1.24 (3H, t J=7.06 Hz), 1.70-1.90 (1H, m), 2.05-2.26 (1H, m), 2.26(2H, d J=6.64 Hz), 2.46-2.67 (2H, m), 2.67-2.71 (1H, m), 2.80-2.88 (1H,m), 4.16 (1H, d J=7.06 Hz), 6.49 (1H, d J=15.90 Hz), 6.70 (1H, d J=6.98Hz), 7.52 (1H, d J=15.90 Hz), 8.10 (1H, d J=1.90 Hz), 8.28 (1H, d J=1.90Hz).

Preparation 597

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.06-1.28 (2H, m), 1.24 (3H, t J=7.06 Hz), 1.47-2.50(14H, m), 2.55-2.69 (1H, m), 2.70-2.82 (1H, m), 4.16 (2H, q J=7.06 Hz),6.49 (1H, d J=15.92 Hz), 6.66 (1H, d J=7.02 Hz), 7.52 (1H, d J=15.92Hz), 8.10 (1H, d J=1.92 Hz), 8.28 (1H, d J=1.92 Hz).

Preparation 598

A solution of ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(820 mg) and 1N NaOH solution (4.1 ml) in MeOH (20 ml) was stirred at80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo andthe residue was dissolved in a mixture of AcOEt and brine. The aquoussolution was adjusted to PH 5.4 with 5% HCl solution and extracted withTHF and AcOEt. The solvent was evaporated in vacuo and The precipitatewas washed with n-hexane to give(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (410 mg).

¹H-NMR (DMSO-d6): δ 1.76-1.90 (1H, m), 2.17-2.29 (1H, m), 2.49 (3H, s),2.49-2.61 (2H, m), 2.74-2.77 (1H, m), 2.87-2.95 (1H, m), 3.60 (2H, s),4.46-4.58 (1H, m), 6.39 (1H, d J=15.92 Hz), 6.75 (1H, d J=6.88 Hz),7.05-7.25 (4H, m), 7.45 (1H, d J=15.92 Hz), 8.07 (1H, d J=1.82 Hz), 8.24(1H, d J=1.82 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 598.

Preparation 599

(2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]acrylic acid

¹H-NMR (DMSO-d6): δ 1.54-1.71 (6H, m), 1.90-2.00 (2H, m), 4.32-4.46 (1H,m), 6.38 (1H, d J=15.84 Hz), 6.60 (1H, d J=7.26 Hz), 7.47 (1H; d J=15.84Hz), 8.04 (1H, d J=1.96 Hz), 8.25 (1H, d J=1.96 Hz).

Preparation 600

(2E)-3-{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}acrylicacid

¹H-NMR (DMSO-d6): δ 0.97 (9H, s), 1.02-1.99 (9H, m), 3.85-3.98 & 4.20(total 1H, each m), 5.78 & 6.50 (total 1H, each d J=6.58 Hz), 6.36 &6.58 (total 1H, each d J=15.96 Hz), 7.45 & 7.47 (total 1H, each dJ=15.96 Hz), 8.03 & 8.11 (total 1H, each d J=1.90 Hz), 8.23 & 8.28(total 1H, each d J=1.90 Hz).

Preparation 601

(2E)-3-(5-chloro-6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.76-1.93 (1H, m), 2.19-2.26 (1H, m), 2.50-2.63 (2H,m), 2.77-2.80 (1H, m), 2.91-2.99 (1H, m), 3.73 (2H, s), 4.53-4.61 (1H,m), 6.41 (1H, d J=15.94 Hz), 6.78 (1H, d J=6.90 Hz), 6.88-7.22 (3H, m),7.33-7.40 (1H, m), 7.47 (1H, d J=15.94 Hz), 8.07 (1H, d J=1.84 Hz), 8.25(1H, d J=1.84 Hz).

Preparation 602

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.14-1.36 (6H, m), 1.66-1.69 (4H, m), 1.91-2.18 (3H,m), 3.27-3.71 (4H, m), 4.52-4.72 (1H, m), 6.42 (1H, d J=15.90 Hz),6.87-6.98 (1H, m), 7.48 (1H, d J=15.90 Hz), 8.10 (1H, d J=1.92 Hz), 8.28(1H, d J=1.92 Hz), 12.21 (1H, br.s).

Preparation 603

(2E)-3-[5-chloro-6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylicacid

¹H-NMR (DMSO-d6): δ 1.90-2.06 (2H, m), 2.39 (3H, s), 3.09-3.52 (4H, m),4.28-4.37 (1H, m), 6.42 (1H, d J=15.90 Hz), 6.61 (1H, d J=5.92 Hz), 7.36(2H, d J=8.14 Hz), 7.47 (1H, d J=15.90 Hz), 7.64 (2H, d J=8.14 Hz), 8.06(1H, d J=1.90 Hz), 8.24 (1H, d J=1.90 Hz), 12.23 (1H, br.s).

Preparation 604

(2E)-3-[6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylicacid

¹H-NMR (DMSO-d6): δ 1.72-1.74° (1H, m), 1.91-2.02 (1H, m), 2.39 (3H, s),3.03-3.10 (1H, m), 3.19-3.45 (3H, m), 4.18-4.26 (1H, m), 6.26 (1H, dJ=15.82 Hz), 6.41 (1H, d J=8.82 Hz), 7.28 (1H, m), 7.38 (2H, d J=8.06Hz), 7.46 (1H, d J=15.82 Hz), 7.65 (2H, d J=8.06 Hz), 7.78 (1H, ddJ=2.04 Hz, 8.82 Hz), 8.18 (1H, d J=2.04 Hz).

Preparation 605

(2E)-3-(6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.36-1.49 (6H, m), 1.71-1.91 (1H, m), 1.99-2.13 (1H,m), 3.12-3.17 (4H, m), 3.34-3.47 (3H, m), 3.57-3.66 (1H, m), 4.30-4.36(1H, m), 6.25 (1H, d J=15.92 Hz), 6.55 (1H, d J=8.86 Hz), 7.38 (1H, dJ=6.16 Hz), 7.46 (1H, d J=15.92 Hz), 7.79 (1H, dd J=2.08 Hz, 8.86 Hz),8.21 (1H, d J=2.08 Hz), 12.06 (1H, s).

Preparation 606

(2E)-3-(5-chloro-6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.76 (6H, br.s), 1.91-2.12 (2H, m), 3.12 (4H, br.s),3.25-3.43 (3H, m), 3.53-3.62 (1H, m), 4.46-4.56 (1H, m), 6.41 (1H, dJ=15.98 Hz), 6.69 (1H, d J=6.40 Hz), 7.47 (1H, d J=15.98 Hz), 8.09 (1H,d J=1.84 Hz), 8.28 (1H, d J=1.84 Hz).

Preparation 607

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.49-1.77 (8H, m), 1.90-2.30 (2H, m), 2.70-2.86 (1H,m), 3.28-3.67 (3H, m), 3.68-3.84 (1H, m), 4.49-4.68 (1H, m), 6.42 (1H, dJ=15.96 Hz), 6.87-6.98 (1H, m), 7.48 (1H, d J=15.96 Hz), 8.10 (1H, dJ=1.76 Hz), 8.29 (1H, d J=1.78 Hz), 12.15 (1H, br.s).

Preparation 608

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 1.72-2.18 (9H, m), 3.21-3.71 (4H, m), 4.48-4.64 (1H,m), 6.41 (1H, d J=15.94 Hz), 6.85-6.97 (1H, m), 7.44 (1H, d J=15.94 Hz),8.11 (1H, s), 8.29 (1H, s), 12.21 (1H, br.s).

Preparation-609

(2E)-3-(5-chloro-6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 2.12-2.18 (2H, m), 3.38-3.66 (4H, m), 4.54-4.69 (1H,m), 6.36-6.47 (1H, m), 6.88-7.07 (1H, m), 7.40-7.59 (5H, m), 8.09 & 8.12(total 1H, each s), 8.22- & 8.31 (total 1H, each s).

Preparation 610

(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl}acrylicacid

¹H-NMR (DMSO-d6): δ 2.06-2.31 (2H, m), 3.55-3.70 (3H, m), 3.84-3.93 (1H,m), 4.67-4.77 (1H, m), 6.42 (1H, d J=15.90 Hz), 6.49-6.59 (1H, m), 7.00(1H, d J=6.42 Hz), 7.49 (1H, d J=15.90 Hz), 8.10 (1H, d J=1.90 Hz),8.31-8.46 (3H, m), 12.17 (1H, br, s).

Preparation 611

(2E)-3-(5-chloro-6-{[(3R)-1-(4-fluorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 2.09-2.21 (2H, m), 3.34-3.76 (4H, m), 4.54-4.68 (1H,m), 6.39 & 6.43 (total 1H, each d J=15.96 Hz), 6.98 & 7.04 (total 1H,each d J=6.32 Hz), 7.21 (2H, m), 7.44 & 7.49 (total 1H, each d J=15.96Hz), 7.56-7.65 (2H, m), 8.08 & 8.11 (total 1H, each s), 8.22 & 8.31(total 1H, each s), 12.26 (1H, br.s).

Preparation 612

(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 2.09-2.21 (2H, m), 2.32 & 2.35 (total 1H, each s),3.36-3.74 (4H, m), 4.52-4.69 (1H, m), 6.39 & 6.43 (total 1H, each dJ=15.92 Hz), 6.97 & 7.03 (total 1H, each d J=6.52 Hz), 7.29-7.36 (4H,m), 7.43 & 7.49 (total 1H, d each d J=15.92 Hz), 8.08 & 8.12 (total 1H,each d J=1.40 Hz), 8.23 & 8.31 (total 1H, each d J=1.40 Hz), 12.20 (1H,br.s).

Preparation 613

(2E)-3-(5-chloro-6-{[(3R)-1-(3-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): δ 2.09-2.19 (2H, m), 3.35-3.73 (4H, m), 4.55-4.70 (1H,m), 6.40 & 6.43 (total 1H, each d J=15.96 Hz), 6.93 & 7.00 (total 1H,each d J=6.26 Hz), 7.36-7.57 (5H, m), 8.08 & 8.12 (total 1H, each dJ=1.70 Hz), 8.23 & 8.31 (total 1H, each d J=1.70 Hz), 12.19 (1H, br.s).

Preparation 614

(2E)-3-(5-chloro-6-{[(3R)-1-(2-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (DMSO-d6): 2.07-2.18 (2H, m), 3.09-3.56 (3H, m), 3.83-3.86 (1H,m), 4.57-4.67 (1H, m), 6.40 & 6.43 (total 1H, each d J=15.96 Hz), 6.93 &7.00 (total 1H, each d J=6.40 Hz), 7.36-7.57 (5H, m), 8.08 & 8.11 (total1H, each d J=1.86 Hz), 8.22 & 8.31 (total 1H, each d J=1.86 Hz), 12.19(1H, br.s).

Preparation 615

A mixture of A mixture of(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (410 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (142 mg), HOBt(156 mg) and EDCI (180 mg) in DMF (15 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof AcOEt-H₂O and the organic layer was washed with brine and dried overMgSO₄. The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with AcOEt-MeOH (9:1). The elutedfractions containing the desired product were collected and evaporatedin vacuo to give(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(400 mg).

¹H-NMR (DMSO-d6): δ 1.23-1.84 (7H, m), 2.09-2.29 (1H, m), 2.29 (3H, s),2.37-2.53 (2H, m), 2.63-2.65 (1H, m), 2.74-2.89 (1H, m), 3.55 (2H, s),3.30-3.57 (2H, m), 3.94-4.01 (1H, m), 4.44-4.55 (1H, m), 4.89 (1H, s),6.32 (1H, d J=15.64 Hz), 6.61 (1H, d J=6.88 Hz), 7.02-7.23 (4H, m), 7.36(1H, d J=15.64 Hz), 7.84 (1H, s), 7.20 (1H, s), 11.07 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 615.

Preparation 616

(2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53-1.84 (12H, m), 1.89-1.99 (2H, m), 3.49-3.55(1H, m), 3.93-4.05 (1H, m), 4.30-4.41 (1H, m), 4.89 (1H, s), 6.31 (1H, dJ=15.76 Hz), 6.54 (1H, d J=7.26 Hz), 7.36 (1H, d J=15.76 Hz), 7.82 (1H,s), 8.21 (1H, s), 11.07 (1H, s).

Preparation 617

(2E)-3-{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 0.85 (9H, s), 1.00-2.00 (15H, m), 3.49-3.55 (1H, m),3.86-4.20 (2H, m), 4.89 (1H, s), 5.70 & 6.43 (total 1H, each d J=6.58Hz), 6.34-6.41 (1H, m), 7.32-7.40 (1H, m), 7.82 & 7.87 (total 1H, eachs), 8.19 & 8.23 (total 1H, each s), 11.07 (1H, s).

Preparation 618

A mixture of(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (306 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (108 mg) HOBt(119 mg) and EDCI (137 mg) in DMF (15 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof AcOEt-H₂O and the organic layer was washed with brine and dried overMgSO₄. The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with AcOEt-MeOH (9:1). The elutedfractions containing the desired product were collected and evaporatedin vacuo to give(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(100 mg).

¹H-NMR (DMSO-d6): δ 0.64-0.92 (2H, m), 1.02-1.23 (4H, m), 1.23-1.91(12H, m), 2.09-3.06 (7H, m), 3.49-3.55 (1H, m), 3.95-4.02 (1H, m),4.48-4.56 (1H, m), 4.89 (1H, s), 6.32 (1H, d J=15.76 Hz), 6.59 (1H, dJ=5.04 Hz), 7.36 (1H, d J=15.76 Hz), 7.85 (1H, s), 8.21 (1H, s), 11.08(1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 618.

Preparation 619

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53-2.09 (15H, m), 2.39-2.52 (6H, m), 2.78-2.79(1H, m), 3.36-3.55 (3H, m), 3.93-3.49 (1H, m), 4.39-4.46 (1H, m), 4.89(1H, s), 6.32 (1H, d J=15.80 Hz), 6.58 (1H, d J=7.00 Hz), 7.36 (1H, dJ=15.80 Hz), 7.84 (1H, d J=1.60 Hz), 8.21 (1H, d J=1.60 Hz), 11.07 (1H,br.s).

Preparation 620

(2E)-3-(5-chloro-6-{[(3R)-1-(3-methyl-2-buten-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.14-1.91 (7H, m), 1.63 (3H, s), 1.69 (3H, s),2.09-2.16 (1H, m), 2.49-2.57 (2H, m), 2.73-2.92 (2H, m), 2.92-3.10 (2H,m), 3.49-3.51 (1H, m), 3.95 (1H, m), 4.48-4.52 (1H, m), 4.89 (1H, s),5.24-5.27 (1H, m), 6.33 (1H, d J=15.74 Hz), 6.65 (1H, d J=6.90 Hz), 7.36(1H, d J=15.74 Hz), 7.86 (1H, s), 8.21 (1H, s), 11.08 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 615.

Preparation 621

(2E)-3-(5-chloro-6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.22-2.00 (7H, m), 2.18-2.20 (1H, m), 2.41-2.52 (2H,m), 2.61-2.68 (1H, m), 2.81-2.90 (1H, m), 3.50-3.55 (2H, m), 3.55 (2H,m), 3.94-4.05 (1H, m), 4.47-4.57 (1H, m), 4.90 (1H, s), 6.33 (1H, dJ=15.66 Hz), 6.65 (1H, d J=6.88 Hz), 7.01-7.18 (3H, m), 7.30-7.41 (2H,m), 7.85 (1H, s), 8.20 (1H, s), 10.96 (1H, s).

Preparation 622

(2E)-3-[5-chloro-6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53-1.69 (6H, m), 1.95-2.05 (2H, m), 2.39 (3H, s),3.11-3.28 (3H, m), 3.34-3.55 (2H, m), 3.96-3.98 (1H, m), 4.30-4.33 (1H,m), 4.89 (1H, s), 6.35 (1H, d J=15.92 Hz), 6.56 (1H, d J=5.78 Hz), 7.36(2H, d J=8.14 Hz), 7.48 (1H d J=15.92 Hz), 7.64 (2H, d J=8.14 Hz), 7.84(1H, s), 8.20 (1H, s), 11.10 (1H, br.s).

Preparation 623

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.14-1.29 (6H, m), 1.53-1.69 (10H, m), 1.96-2.14(3H, m), 3.23-3.96 (6H, m), 4.51-4.68 (1H, m), 4.89 (1H, s), 6.35 (1H, dJ=15.90 Hz), 6.84-6.92 (1H, m), 7.38 (1H, d J=15.90 Hz), 7.88 (1H, s),8.25 (1H, s), 11.10 (1H, s).

Preparation 624

(2E)-3-[6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.52-1.77 (7H, m), 1.99-2.02 (1H, m), 2.39 (3H, s),3.02-3.09 (1H, m), 3.20-3.55 (4H, m), 3.98-4.01 (1H, m), 4.20-4.23 (1H,m), 4.88 (1H, s), 6.24 (1H, d J=15.48 Hz), 6.40 (1H, d J=8.76 Hz), 7.13(1H, d J=5.74 Hz), 7.36 (1H, d J=15.48 Hz), 7.38 (2H, d J=8.18 Hz), 7.61(1H, d J=8.76 Hz), 7.65 (2H, d J=8.18 Hz), 8.18 (1H, s), 11.07 (1H, s).

Preparation 625

(2E)-3-(6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.23-1.84 (13H, m), 2.07-2.09 (1H, m), 3.11 (4H, m),3.35-3.66 (4H, m), 3.93-3.95 (1H, m), 4.30-4.35 (1H, m), 4.88 (1H, s),6.24 (1H, d J=15.44 Hz), 6.55 (1H, d J=8.80 Hz), 7.28 (1H, d J=6.24 Hz),7.37 (1H, d J=15.44 Hz), 7.63 (1H, d J=8.80 Hz), 8.17 (1H, s), 11.06(1H, s).

Preparation 626

(2E)-3-(5-chloro-6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.14-1.70 (12H, m), 1.85-2.12 (2H, m), 3.08 (4H,br.s), 3.25-3.62 (4H, m), 3.98-4.01 (1H, m), 4.44-4.48 (1H, m), 4.90(1H, s), 6.35 (1H, d J=15.78 Hz), 6.81 (1H, d J=6.58 Hz), 7.38 (1H, dJ=15.78 Hz), 7.96 (1H, s), 8.24 (1H, s), 11.08 (1H, br.s).

Preparation 627

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53-1.69 (14H, m), 1.99-2.12 (2H, m), 2.73-2.89(1H, m), 3.28-4.00 (6H, m), 4.51-4.70 (1H, m), 4.89 (1H, s), 6.35 (1H, dJ=15.84 Hz), 6.85-6.92 (1H, m), 7.38 (1H, d J=15.84 Hz), 7.88 (1H, s),8.25 (1H, s), 11.09 (1H, br.s).

Preparation 628

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): 1.53-2.18 (15H, m), 3.25-3.71 (4H, m), 3.93-3.95 (1H,m), 4.50-4.60 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.98 Hz), 6.84-6.91(1H, m), 7.38 (1H, d J=15.98 Hz), 7.95 (1H, s), 8.24 (1H, s), 11.08 (1H,br.s).

The following compounds were obtained in a similar manner to that ofPreparation 618.

Preparation 629

(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyridinylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53-1.99 (8H, m), 2.00-2.18 (1H, m), 2.47-2.58 (2H,m), 2.69-2.73 (1H, m), 2.86-2.94 (1H, m), 3.34 (2H, s), 3.49-3.50 (1H,m), 3.98-4.05 (1H, m), 4.50-4.56 (1H, m), 4.89 (1H, s), 6.36 (1H, dJ=15.90 Hz), 6.96, (1H, d J=6.90 Hz), 7.22-7.28 (1H, m), 7.41-7.45 (1H,m), 7.72-7.85 (2H, m), 7.96 (1H, s), 8.26 (1H, s), 8.46-8.50 (1H, m),11.07 (1H, br.s).

The following compound was obtained in a similar manner to that ofPreparation 615.

Preparation 630

(2E)-3-(5-chloro-6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.69-1.74 (6H, m), 1.99-2.21 (2H, m), 3.34-3.91 (5H,m), 4.54-4.72 (2H, m), 4.89 (1H, s), 6.28-6.36 (1H, m), 6.91-6.97 (1H,m), 7.31-7.60 (5H, m), 7.86-7.96 (1H, m), 8.11-8.27 (1H, m), 11.09 (1H,s).

The following compounds were obtained in a similar manner to that ofPreparation 618.

Preparation 631

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 0.04-0.11 (2H, m), 0.39-0.48 (2H, m), 0.70-0.90 (1H,m), 1.53-1.90 (7H, m), 2.09-2.24 (1H, m), 2.26 (2H, d J=6.62 Hz),2.46-2.52 (2H, m), 2.68-2.71 (1H, m), 2.80-2.88 (1H, m), 3.34-3.49 (1H,m), 3.93-3.96 (1H, m), 4.47-4.58 (1H, m), 4.89 (1H, s), 6.33 (1H, dJ=15.78 Hz), 6.59 (1H, d J=6.98 Hz), 7.37 (1H, d J=15.78 Hz), 7.85 (1H,s), 8.22 (1H, s), 11.07 (1H, br.s).

Preparation 632

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6) δ 1.16-1.21 (2H, m), 1.49-2.52 (20H, m), 2.52-2.69 (1H,m), 2.70-2.90 (1H, m), 3.49-3.55 (1H, m), 3.94-3.99 (1H, m), 4.41-4.47(1H, m), 4.89 (1H, s), 6.34 (1H, d J=15.78 Hz), 6.55 (1H, d J=7.04 Hz),7.33 (1H, d J=15.78 Hz), 7.85 (1H, s), 8.21 (1H, s), 11.07 (1H, br.s).

The following compounds were obtained in a similar manner to that ofPreparation 615.

Preparation 633

(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.54 (3H, br.s), 1.69 (1H, br.s), 1.74-2.09 (1H, m),2.15-2.17 (1H, m), 3.35-3.55 (3H, m), 3.67-3.69 (1H, m), 3.86-3.96 (2H,m), 4.66-4.71 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.78 Hz), 6.58-6.60(1H, m), 6.95 (1H, d J=6.40 Hz), 7.88 (1H, s), 8.27 (1H, s), 8.32-8.33(2H, m), 11.11 (1H, s).

Preparation 634

(2E)-3-(5-chloro-6-{[(3R)-1-(4-fluorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53 (3H, s), 1.69 (3H, s), 2.09-2.15 (2H, m),3.35-3.59 (4H, m), 3.59-3.95 (2H, m), 4.53-4.68 (1H, m), 4.90 (1H, s),6.30-6.34 (1H, m), 6.93 & 6.99 (total 1H, each d J=6.06 Hz), 7.27-7.41(3H, m), 7.58-7.64 (2H, m), 7.86 & 7.89 (total 1H, each s), 8.18 & 8.27(total 1H, each s), 11.10 (1H, s).

Preparation 635

(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53 (3H, s), 1.69 (3H, s), 1.99-2.11 (2H, m), 2.32& 2.35 (total 3H, each s), 3.30-3.55 (4H, m), 3.71-4.02 (2H, m),4.52-4.54 (1H, m), 4.89 (1H, s), 6.30-6.37 (1H, m), 6.91 & 6.98 (total1H, each d J=6.12 Hz), 7.24-7.47 (5H, m), 7.85 & 7.89 (total 1H, eachs), 8.17 & 8.27 (total 1H, each s), 11.10 (1H, s).

Preparation 636

(2E)-3-(5-chloro-6-{[(3R)-1-(3-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53 (3H, s), 1.69 (3H, s), 1.99-2.22 (2H, m),3.35-3.58 (4H, m), 3.72-4.04 (2H, m), 4.55-4.68 (1H, m), 4.89 (1H, s),6.30-6.34 (1H, m), 6.93 & 7.02 (total 1H, each d J=6.10 Hz), 7.33-7.58(5H, m), 7.85 & 7.89 (total 1H, each s), 8.19 & 8.27 (total 1H, each s),11.10 (1H, s).

Preparation 637

(2E)-3-(5-chloro-6-{[(3R)-1-(2-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.53 (3H, s), 1.69 (3H, s), 2.09-2.17 (2H, m),3.16-3.55 (4H, m), 3.87-4.04 (2H, m), 4.58-4.66 (1H, m), 4.90 (1H, s),6.34 (1H, m), 6.87-6.94 (1H, m), 7.37-7.53 (5H, m), 7.86 & 7.90 (total1H, each s), 8.17 & 8.27 (total 1H, each s), 11.11 (1H, s).

Preparation 638

A solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (560 mg), p-toluenesulfonyl chloride (318 mg) and Et₃N(0.7 ml) in DMF (15 ml) was stirred at ambient temperature for 10 hours.The reaction mixture was poured into a mixture of AcOEt and H₂O and theorganic layer was washed with brine and dried over MgSO₄. The solventwas evaporated in vacuo and the residue was crystallized fromAcOEt-n-hexane to give ethyl(2E)-3-[5-chloro-6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylate(490 mg).

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.12 Hz), 1.98-2.05 (2H, m), 2.38 (3H,s), 3.14-3.17 (1H, m), 3.23-3.34 (2H, m), 3.45-3.49 (1H, m), 4.16 (2H, qJ=7.12 Hz), 4.32-4.33 (1H, m), 6.53 (1H, d J=15.96 Hz), 6.65 (1H, dJ=5.92 Hz), 7.36 (2H, d J=8.12 Hz), 7.54 (1H, d J=15.96 Hz), 7.62 (2H, dJ=8.12 Hz), 8.11 (1H, d J=1.96 Hz), 8.27 (1H, d J=1.96 Hz).

The following compound was obtained in a similar manner to that ofPreparation 638.

Preparation 639

ethyl(2E)-3-[6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t=7.06 Hz), 1.68-1.82 (1H, m), 1.92-2.22(1H, m), 2.39 (3H, s), 3.04-3.11 (1H, m), 3.21-3.45 (3H, m), 4.18 (2H, qJ=7.06 Hz), 6.34 (1H, d J=15.90 Hz), 6.39 (1H, d J=8.76 Hz), 7.23 (1H, dJ=5.86 Hz), 7.38 (2H, d J=8.08 Hz), 7.52 (1H, d J=15.90 Hz), 7.65 (2H, dJ=8.08 Hz), 7.79 (1H, dd J=2.08 Hz, 8.78 Hz), 8.21 (1H, d J=2.08 Hz).

Preparation 640

A solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (610 mg), cyclohexanecarbonyl chloride (267 mg) and Et₃N(0.76 ml) in DMF (15 ml) was stirred at ambient temperature for 8 hours.The reaction mixture was poured into a mixture of AcOEt and H₂O and theorganic layer was washed with brine and dried over MgSO₄ The solvent wasevaporated in vacuo and the residue was chromatographed on silicageleluting with AcOEt-MeOH (95:5). The eluted fractions containing thedesired product were collected and evaporated in vacuo to give ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(630 mg).

¹H-NMR (DMSO-d6): δ 1.21-1.31 (6H, m), 1.25 (3H, t J=7.08 Hz), 1.63-1.69(5H, m), 1.93-2.10 (2H, m), 3.28-3.84 (4H, m), 4.15 (2H, q J=7.08 Hz),4.67-4.68 (1H, m), 6.52 (1H, d J=15.98 Hz), 6.95-7.19 (1H, m), 7.53 (1H,d J=15.98 Hz), 8.14 (1H, d J=1.86 Hz), 8.32 (1H, d J=1.86 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 640.

Preparation 641

ethyl(2E)-3-(6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.49 (6H, br.s), 1.70-1.89(1H, m), 2.00-2.16 (1H, m), 3.15 (4H, br, s), 3.15-3.46 (3H, m),3.58-3.66 (1H, m), 4.18 (2H, q J=7.06 Hz), 4.34-4.40 (1H, m), 6.34 (1H,d J=15.82 Hz), 6.55 (1H, d J=8.84 Hz), 7.39 (1H, d J=6.28 Hz), 7.52 (1H,d J=15.82 Hz), 7.81 (1H, dd J=2.14 Hz, 8.84 Hz), 8.24 (1H, d J=2.14 Hz).

Preparation 642

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 1.49 (6H, br.s), 1.90-2.12(2H, m), 3.12 (4H, br.s), 3.25-3.43 (3H, m), 3.53-3.62 (1H, m), 4.16(2H, q J=7.08 Hz), 4.46-4.56 (1H, m), 6.51 (1H, d J=15.90 Hz), 6.91 (1H,d J=6.62 Hz), 7.53 (1H, d J=15.90 Hz), 8.13 (1H, d J=1.90 Hz), 8.31 (1H,d J=1.90 Hz).

Preparation 643

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.06 Hz), 1.97-2.18 (9H, m), 3.21-3.60(3H, m), 3.60-3.72 (1H, m), 4.16 (2H, q J=7.06 Hz), 4.52-4.62 (1H, m),6.52 (1H, d J=15.86 Hz), 6.89-7.01 (1H, m), 7.53 (1H, d J=15.86 Hz),8.13 (1H, s), 8.32(1H, s).

Preparation 644

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.06 Hz), 1.49-1.77 (8H, m), 1.90-2.20(2H, m), 2.70-2.86 (1H, m), 3.30-3.51 (3H, m), 3.98-4.02 (1H, m), 4.16(2H, q J=7.06 Hz), 4.53-4.69 (1H, m), 6.52 (1H, d J=15.96 Hz), 6.94-7.02(1H, m), 7.54 (1H, d J=15.96 Hz), 8.13-8.15 (1H, m), 8.31-8.33 (1H, m).

Preparation 645

A solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (500 mg), 4-chlorobenzoyl chloride (249 mg) and Et₃N(0.624 ml) in DMF (20 ml) was stirred at ambient temperature for 10hours. The reaction mixture was poured into a mixture of AcOEt and H₂Oand the organic layer was washed with brine and dried over MgSO₄. Thesolvent was evaporated in vacuo and the residue was washed with IPE andn-hexane to give ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(570 mg).

¹H-NMR (DMSO-d6): δ 1.20-1.28 (3H, m), 2.11-2.18 (2H, m), 3.34-3.63 (4H,m), 4.10-4.18 (2H, m), 4.43-4.71 (1H, m), 6.46-6.57 (1H, m), 7.00-7.07(1H, m), 7.46-7.60 (5H, m), 8.11-8.18 (1H, m), 8.25 & 8.34 (total 1H,each s).

The following compounds were obtained in a similar manner to that ofPreparation 645.

Preparation 646

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(4-fluorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 2.00-2.16 (2H, m), 3.35-3.78(4H, m), 4.15 (2H, q J=7.08 Hz), 4.56-4.70 (1H, m), 6.50 & 6.54 (total1H, each d J=15.88 Hz), 7.03 & 7.04 (total 1H, each d J=6.32 Hz),7.23-7.28 (2H, m), 7.48-7.63 (3H, m), 8.12 & 8.16 (total 1H, each dJ=1.72 Hz), 8.26.& 8.34 (total 1H, each d J=1.72 Hz).

Preparation 647

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): 1.24 (3H, t J=7.08 Hz), 2.03-2.14 (2H, m), 2.31 & 2.35(total 3H, each s), 3.43-3.73 (4H, m), 4.15 (2H, q J=7.08 Hz), 4.53-4.70(1H, m), 6.50 & 6.54 (total 1H, each d J=15.86 Hz), 7.01 & 7.08 (total1H, each d J=6.56 Hz), 7.24-7.33 (4H, m), 7.49 & 7.54 (total 1H, each dJ=15.86 Hz), 8.12 & 8.16 (total 1H, each d J=1.76 Hz), 8.25 & 8.34(total 1H, each d J=1.76 Hz).

Preparation 648

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(3-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.99-2.30 (2H, m), 3.34-3.58(3H, m), 3.58-3.74 (1H, m), 4.15 (2H, q J=7.06 Hz), 4.56-4.70 (1H, m),6.50 & 6.53 (total 1H, each d J=15.92 Hz), 7.03 & 7.04 (total 1H, each dJ=6.32 Hz), 7.47-7.58 (5H, m), 8.12 & 8.16 (total 1H, each d J=1.92 Hz),8.26 & 8.34 (total 1H, each d J=1.92 Hz).

Preparation 649

ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(2-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (DMSO-d6): 1.24 (3H, t J=7.06 Hz), 2.09-2.17 (2H, m), 3.13-3.43(2H, m), 3.40-3.55 (1H, m), 3.70-3.76 (1H, m), 4.15 (2H, q J=7.06 Hz),4.56-4.70 (1H, m), 6.50 & 6.54 (total 1H, each d J=16.00 Hz), 6.97 &6.99 (total 1H, each d, J=6.52 Hz), 7.38-7.52 (5H, m), 8.12 & 8.16(total 1H, each d J=2.00 Hz), 8.25 & 8.34 (total 1H, each d J=2.00 Hz).

Preparation 650

A solution of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (700 mg), 2-chloropyrimidine (283 mg) andN,N-diisopropylethylamine (1.09 ml) in DMF (20 ml) was stirred at 80-85°C. for 12 hours under atmospheric pressure of nitrogen. The reactionmixture was poured into a mixture of AcOEt and H₂O and the organic layerwas washed with brine and dried over MgSO₄. The solvent was evaporatedin vacuo and the residue was chromatographed on silicagel eluting withAcOEt. The eluted fractions containing the desired product werecollected and evaporated in vacuo to give ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(0.560 mg).

¹H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.12 Hz), 2.16-2.27 (2H, m), 3.35-3.56(2H, m), 3.67-3.70 (1H, m), 3.84-3.93 (1H, m), 4.17 (2H, q J=7.12 Hz),4.65-4.71 (1H, m), 6.52 (1H, d J=16.12 Hz), 6.60 (1H, d J=4.48 Hz), 7.04(1H, d J=6.42 Hz), 7.54 (1H, d J=16.14 Hz), 8.32-8.35 (3H, m).

Preparation 651

To a mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (2.08 g) andmagnesium bromide (1.9 g) in THF (20 ml) was added dropwise to a Et3N(1.32 ml) with stirring at 0-15° C. under atmospheric pressure ofnitrogen, and the reaction mixture was stirred at same condition for anhour. A solution of tert-butyl(3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate(2.0 g) in THF (10 ml) solution was added the above mixture andresultant mixture was stirred at 0-15° C. for 4 hours. The reactionmixture was poured into a mixture of AcOEt-H₂O and the organic layer waswashed with brine and dried over MgSO₄. The solvent was evaporated invacuo and the residue was chromatographed on silicagel eluting withAcOEt-n-hexane (3:7). The eluted fractions containing the desiredproduct were collected and evaporated in vacuo to give tert-butyl(3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(2.34 g)

¹H-NMR (CDCl₃): δ 1.37 (3H, t J=7.08 Hz), 1.40 (9H, s), 1.96 (1H, m),2.24-2.33 (1H, m), 3.21-3.35 (1H, m), 3.48-3.55 (2H, m), 3.76-3.81 (1H,m), 4.34 (2H, q J=7.08 Hz), 4.66-4.67 (1H, m), 5.30-5.32 (1H, m), 6.78(1H, d J=35.36 Hz), 7.90 (1H, d J=1.64 Hz), 8.15 (1H, d J=1.64 Hz).

Preparation 652

A mixture of tert-butyl(3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(2.34 g) and 4N hydrogen chloride in dioxane solution (11 ml) in EtOH(10 ml) was stirred at ambient temperature for 4 hours. IPE (100 ml) wasadded to a reaction mixture and the precipitate was collected byfiltration to give ethyl(2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylatedihydrochloride (1.95 g).

¹H-NMR (DMSO-d6): δ 1.29 (3H, t J=70.10 Hz), 2.03-2.04 (1H, m),2.22-2.26 (1H, m), 3.19-3.25 (2H, m), 3.35-3.57 (2H, m), 4.28 (2H, qJ=7.10 Hz), 4.73-4.86 (1H, m), 7.03 (1H, d J=37.48 Hz), 7.97 (1H, dJ=1.82 Hz), 8.38 (1H, d J=1.82 Hz), 9.65 (2H, br.s).

Preparation 653

A mixture of ethyl(2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylatedihydrochloride (720 mg), cyclopentanone (188 mg), sodiumtriacetoxyborohydride (1.18 g) and Et₃N (0.52 ml) in CHCl₃ (20 ml) wasstirred at 25-30° C. for 15 hours. The 10% K₂CO₃ solution (20 ml) wasadded to a reaction mixture and stirred at ambient temperature for 30minutes and extracted with CH₂Cl₂ and washed with brine and dried overMgSO₄. The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with CHCl₃-MeOH (96:4). The elutedfractions containing the desired product were collected and evaporatedin vacuo to give ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(710 mg).

¹H-NMR (CDCl₃): δ 1.37 (3H, t J=7.16 Hz), 1.53-1.57 (3H, m), 1.71-1.74(5H, m), 2.39-2.42 (3H, m), 2.73-2.81 (2H, m), 2.95 (1H, m), 4.33 (2H, qJ=7.16 Hz), 4.64-4.68 (1H, m), 5.61-5.63 (1H, m), 6.76 (1H, d J=35.52Hz), 7.87 (1H, d J=1.84 Hz), 8.15 (1H, d J=1.84 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 653.

Preparation 654

ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR (CDCl₃): δ 1.21-1.28 (4H, m), 1.37 (3H, t J=7.16 Hz), 1.73-1.77(4H, m), 1.93 (2H, m), 2.17 (1H, m), 2.42-2.45 (2H, m), 2.78-2.85 (2H,m), 3.00 (1H, m), 4.33 (2H, q J=7.16 Hz), 4.62-4.66 (1H, m), 5.61-5.63(1H, m), 6.76 (1H, d J=35.52 Hz), 7.87 (1H, d J=1.84 Hz), 8.15 (1H, dJ=1.84 Hz).

Preparation 655

ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR (CDCl₃): δ 0.88-0.91 (2H, m), 1.19-1.21 (3H, m), 1.37 (3H, tJ=7.16 Hz), 1.40-1.60 (1H, m), 1.68-1.73 (6H, m), 2.27-2.34 (4H, m),2.65-2.66 (2H, m), 2.89 (1H, m), 4.33 (2H, q J=7.16 Hz), 4.62-4.67 (1H,m), 5.63-5.65 (1H, m), 6.77 (1H, d J=35.52 Hz), 7.87 (1H, d J=1.76 Hz),8.17 (1H, d J=1.76 Hz).

Preparation 656

A mixture of ethyl(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate(710 mg) and 1N NaOH solution (3.8 ml) in MeOH (20 ml) was stirred at75-80° C. for 2 hours. To the reaction mixture was added 1N HCl solution(3.8 ml) and the resultant solution was evaporated in vacuo and theresidue was dissolved in a mixture of MeOH and toluene and evaporated invacuo and the residue was dried to give(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (658 mg).

¹H-NMR (DMSO-d6): δ 1.75-2.12 (9H, m), 2.35-2.52 (2H, m), 2.99-3.81 (4H,m), 4.78-4.91 (1H, m), 6.67 (1H, d J=37.52 Hz), 7.09 (1H, d J=7.34 Hz),7.86 (1H, d J=1.64 Hz), 8.24 (1H, d J=1.64 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 656.

Preparation 657

(2Z)-3-(5-chloro-6-{([(3R)-1-cyclohexyl-3-pyrrolidinyl}amino]-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR (DMSO-d6): δ 1.06-1.62 (7H, m), 1.76-1.81 (2H, m), 1.97-2.06 (2H,m), 2.30-2.50 (2H, m), 3.04-3.52 (4H, m), 4.77-4.80 (1H, m), 6.66 (1H, dJ=37.56 Hz), 7.09 (1H, d. J=7.33 Hz), 7.86 (1H, d J=1.28 Hz), 8.23 (1H,d J=1.28 Hz).

Preparation 658

(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR (DMSO-d6): δ 0.89-1.26 (6H, m), 1.64-2.06 (7H, m), 2.30-2.44 (2H,m), 2.84-2.88 (2H, m), 3.17-3.20 (1H, m), 3.40 (1H, m), 4.76-4.79 (1H,m), 6.69 (1H, d J=37.54 Hz), 7.06 (1H, d J=7.21 Hz), 7.87 (1H, d J=1.68Hz), 8.24 (1H, d J=1.68 Hz).

Preparation 659

(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR (DMSO-d6): δ 1.99-2.11 (1H, m), 2.30-2.41 (1H, m), 3.11-3.52 (4H,m), 4.30 (2H, s), 4.71-4.81 (1H, m), 6.82 (1H, d J=37.42 Hz), 7.11-7.29(3H, m), 7.40-7.47 (2H, m), 7.60-7.62 (1H, m), 7.90 (1H, s), 8.28 (1H,s).

Preparation 660

(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid

¹H-NMR (DMSO-d6): δ 1.83-1.89 (1H, m), 2.26-2.36 (1H, m), 2.75-3.28 (4H,m), 3.96-4.09 (2H, m), 4.46-4.49 (1H, m), 6.57 (1H, d J=8.88 Hz), 6.75(1H, d J=37.98 Hz), 7.14-7.51 (6H, m), 7.74 (1H, dd J=1.92 Hz, 8.88 Hz),8.23 (1H, d J=1.92 Hz).

Preparation 661

A mixture of(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylicacid (658 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (229 mg), HOBt(264 mg) and EDCI (303 mg) in DMF (15 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof AcOEt-H₂O and the organic layer was washed with brine and dried overMgSO₄ The solvent was evaporated in vacuo and the residue waschromatographed on silicagel eluting with AcOEt-MeOH (95:5). The elutedfractions containing the desired product were collected and evaporatedin vacuo to give(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(620 mg).

¹H-NMR (DMSO-d6): δ 1.37-1.72 (12H, m), 2.09-2.20 (1H, m), 2.73 (1H, m),2.89 (1H, m), 3.36 (6H, m), 3.50-3.52 (1H, m), 4.05-4.07 (1H, m),4.48-4.50 (1H, m), 4.97 (1H, s), 6.66 (1H, d J=7.00 Hz), 7.85 (1H, dJ=1.88 Hz), 8.28-8.32 (1H, m).

The following compounds were obtained in a similar manner to that ofPreparation 661.

Preparation 662

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.09-1.23 (4H, m), 1.54-1.84 (9H, m), 2.09-2.13 (2H,m), 2.50-2.52 (2H, m), 2.74-2.75 (1H, m), 2.88-2.92 (1H, m), 3.36 (4H,m), 3.36 (4H, m), 3.50-3.53 (1H, m), 4.03-4.08 (1H, m), 4.46-4.50 (1H,m), 4.97 (1H, s), 6.50 (1H, d J=6.96 Hz), 6.78 (1H, d J=39.72 Hz), 7.85(1H, d J=1.88 Hz), 8.29-8.32 (1H, m).

Preparation 663

(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 0.81-0.84 (2H, m), 1.15-1.17 (3H, m), 1.53-1.57 (1H,m), 1.63-1.84 (14H, m), 2.17-2.23 (3H, m), 2.41-2.43 (2H, m), 2.51-2.52(2H, m), 2.74-2.78 (1H, m), 3.50-3.53 (1H, m), 4.07-4.08 (1H, m),4.4974.51 (1H, m), 4.98 (1H, s), 6.62 (1H, d J=7.04 Hz), 6.79 (1H, dJ=69.72 Hz), 7.85 (1H, d J=1.88 Hz), 8.29 (1H, d J=1.88 Hz).

Preparation 664

(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.54 (3H, m), 1.70 (3H, s), 1.81-1.84 (1H, m),2.10-2.22 (1H, m), 2.37-2.40 (2H, m), 2.64-2.65 (1H, m), 2.81-2.85 (1H,m), 3.50-3.52 (1H, m), 3.59 (2H, s), 4.02-4.07 (1H, m), 4.49-4.52 (1H,m), 4.98 (1H, s), 6.68 (1H, d J=6.96 Hz), 6.78 (1H, d J=39.68 Hz),7.21-7.26 (1H, m), 7.28-7.34 (1H, m), 7.85 (1H, d J=1.88 Hz), 8.31 (1H,d J=1.88 Hz).

Preparation 665

(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (DMSO-d6): δ 1.63 (3H, s), 1.64-1.69 (4H, m), 2.20 (1H, m),2.35-2.45 (2H, m), 2.63-2.64 (1H, m), 2.75-2.79 (1H, m), 3.49-3.51 (1H,m), 3.57 (2H, d J=4.76 Hz), 4.03-4.06 (1H, m), 4.32 (1H, m), 4.96 (1H,s), 6.53 (1H, d J=8.90 Hz), 6.69 (1H, d J=40.40 Hz), 7.21-7.26 (2H, m),7.28-7.33 (4H, m), 7.67 (1H, dd J=2.20 Hz, 8.90 Hz), 8.19 (1H, d J=2.20Hz), 11.66 (1H, s).

Preparation 666

To a mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (1.46 g) andmagnesium bromide (1.33 g) in THF (20 ml) was added dropwise to a Et₃N(0.92 ml) with stirring at 0-15° C. under atmospheric pressure ofnitrogen, and the reaction mixture was stirred at same condition for anhour. A solution of6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde (1.36 g)in THF (10 ml) solution was added the above mixture and resultantmixture was stirred at 0-15° C. for 4 hours. The reaction mixture waspoured into a mixture of AcOEt-H₂O and the organic layer was washed withbrine and dried over MgSO₄. The solvent was evaporated in vacuo and theresidue was chromatographed on silicagel eluting with AcOEt-n-hexane(3:7). The eluted fractions containing the desired product werecollected and evaporated in vacuo to give ethyl(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate(1.42 g).

¹H-NMR (CDCl₃): δ 1.36 (3H, t J=7.16 Hz), 1.33-1.39 (1H, m), 1.68-1.73(1H, m), 2.38-2.40 (1H, m), 2.66-2.67 (1H, m), 1.73-2.74 (1H, m), 2.89(1H, m), 3.65 (2H, s), 4.33 (2H, q J=7.16 Hz), 5.69 (1H, d J=7.70 Hz),6.75 (1H, d J=35.52 Hz), 7.23-7.34 (5H, m), 7.86 (1H, d J=1.84 Hz), 8.15(1H, d J=1.84 Hz).

The following compound was obtained in a similar manner to that ofPreparation 666.

Preparation 667

ethyl(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate

¹H-NMR (CDCl₃): δ 1.36 (3H, t J=7.14 Hz), 1.71-1.72 (1H, m), 2.33-2.45(2H, m), 2.57-2.88 (3H, m), 3.64 (2H, s), 4.29 (2H, q J=7.14 Hz), 5.19(1H, d J=7.84 Hz), 6.37 (1H, d J=8.80 Hz), 6.79 (1H, d J=36.28 Hz),7.2-7.33 (5H, m), 7.81 (1H, dd J=20.10 Hz, 8.80 Hz), 8.22 (1H, d J=20.10Hz).

Preparation 668

To a stirred suspension of ethyl(2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride(300 mg) in dichloromethane (6 mL) was added N,N-diisopropylethylamine(348 mg) and phenylacetyl chloride (139 mg) in dichloromethane (1 mL) inan ice bath and the resulting mixture was stirred at the sametemperature for three hours. The mixture was extracted with chloroformand washed with saturated sodium bicarbonate and brine. The organicphase was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate to afford ethyl(2E)-3-(5-{[(3R)-1-(phenylacetyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate(225 mg) as a pale brown viscous oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.3 Hz), 1.35-1.50 (1H, m),1.57-2.03 (3H, m), 3.19-3.57 (2H, m), 3.67-4.67 (4H, m), 4.26 (2H, q,J=7.3 Hz), 4.65 (0.6H, br.d, J=7.0 Hz), 4.98 (0.4H, br.d, J=6.2 Hz),6.69 (0.4H, d, J=15.4 Hz), 6.71 (0.6H, d, J=15.4 Hz), 7.19-7.41 (5H, m),7.57 (0.4H, d, J=15.4 Hz), 7.58 (0.6H, d, J=15.4 Hz), 7.67 (0.6H, br.s),7.87 (0.4H, br.s), 8.03-8.06 (1H, m); MS (ES+) m/z 395.

Preparation 669

A mixture of 5,6-dichloronicotinic acid (356 mg), iodoethane (318 mg)and potassium carbonate (308 mg) in N,N-dimethylformamide (3 mL) washeated at eighty degree for fourteen hours. The mixture was allowed tocool to ambient temperature and to this was added(3R)-1-(cyclohexylmethyl)-3-piperidinamine dihydrochloride (549 mg) andpotassium carbonate (898 mg) and heated at eighty degree for thirtyeighthours. The mixture was allowed to cool to ambient temperature and wasadded water. The mixture was extracted with ethyl acetate (100 mL) andaqueous phase was separated. The organic layer was washed with brine anddried over anhydrous sodium sulfate. The solvent was filtered andevaporated in vacuo to give an amorphous solid. The crude solid waspurified by a flash chromatography eluting with 3% methanol-chloroform(v/v) to give ethyl5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate(154 mg) as a pale yellow amorphous solid.

¹H-NMR (300 MHz, CDCl₃) δ 0.79-0.98 (2H, m), 1.12-1.32 (4H, m), 1.37(3H, t, J=7.3 Hz), 1.43-1.88 (9H, m), 2.03-2.21 (3H, m), 2.33-2.43 (1H,m), 2.59-2.75 (2H, m), 4.33 (2H, q, J=7.3 Hz), 4.36-4.48 (1H, m), 6.36(1H, br.s), 8.00 (1H, d, J=1.8 Hz), 8.66 (1H, d, J=1.8 Hz).

Preparation 670

To a stirred solution of ethyl5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate(321 mg) in tetrahydrofuran (6 mL) was added lithium aluminumhydride(80.2 mg) portionwise in an ice bath and the resulting suspension wasstirred at the same temperature for three hours. To this was addedsaturated aqueous potassium sodium (+)-tartrate tetrahydrate solutionportionwise at the same temperature and the mixture was stirred atambient temperature for one hour. The mixture was extracted with ethylacetate and the aqueous phase was removed. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with ethylacetate-hexane 1:1 (v/v) to afford(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)methanol(210 mg) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃) δ 0.77-0.98 (2H, m), 1.08-1.34 (4H, m),1.39-1.89 (9H, m), 2.03-2.21 (3H, m), 2.34-2.48 (1H, m), 2.52-2.71 (2H,m), 4.17-4.29 (1H, m), 4.52 (2H, s), 5.87 (1H, br.s), 7.51 (1H, d, J=2.2Hz), 7.96 (1H, d, J=2.2 Hz); MS (ES+) m/z 338(M+1).

Preparation 671

To a stirred solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(265 mg, 0.529 mmol) in methanol (5 mL) was added hydroxylaminehydrochloride (184 mg, 2.65 mmol) at ambient temperature. To thismixture was added 1N potassium methoxide in methanol (5.29 mL, 5.29mmol) dropwise in an ice bath and the resulting mixture was stirred atambient temperature for three hours. To the mixture was added 1Nhydrogen chloride to neutralize the solution. The solvent was removed invacuo and the residue was desalted using ion-exchange resin. The crudeproduct was purified by preparative high-pressure liquid chromatographyto afford tert-butyl(5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]carbamate(103 mg) as a colorless wax.

¹H-NMR (300 MHz, DMSO-d6) δ 0.74-0.90 (2H, m), 0.99 (6H, s), 1.09 (6H,s), 1.36 (9H, s), 1.54-1.69 (2H, m), 1.74-2.11 (2H, m), 2.34-2.53 (2H,m), 2.53-2.67 (2H, m), 2.87-2.98 (1H, m), 4.57-4.72 (1H, m), 6.54 (1H,d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.48 (1H, d, J=16.1 Hz), 7.99(1H, dd, 3=8.4, 2.2 Hz), 8.60 (1H, d, J=2.2 Hz); MS (ES+) m/z 488(M+1).

The following compound was obtained in a similar manner to that ofPreparation 671.

Preparation 672

tert-butyl{5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl)[(3R)-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, DMSO-d6) 1.13-1.36 (2H, m), 1.37 (9H, s), 1.60-1.74(2H, m), 1.80-2.21 (3H, m), 2.35-2.67 (3H, m), 2.86-2.97 (1H, m),3.19-3.33 (2H, m), 3.70-3.83 (2H, m), 4.61-4.78 (1H, m), 6.54 (1H, d,J=15.8 Hz), 7.34 (1H, d, J=8.4 Hz), 7.49 (1H, d, J=15.8 Hz), 7.99 (1H,br.d, J=8.8 Hz), 8.61 (1H, br.s); MS (ES+) m/z 433(M+1).

The following compound was obtained in a similar manner to that ofPreparation 871.

Preparation 673

ethyl 6-[(2-benzylphenyl)amino]-5-chloronicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 4.03 (2H, s), 4.34 (2H,q, J=7 Hz), 6.93 (1H, s), 7.14-7.38 (8H, m), 7.88 (1H, d, J=8 Hz), 8.08(1H, d, J=2 Hz), 8.69 (1H, d, J=2 Hz); MS (ES+) m/z 367.

Preparation 674

To a mixture of ethyl5-chloro-6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (395 mg) andammonium formate (472 mg) in ethanol (10 mL) was added 10% palladium oncarbon (40 mg), and the mixture was stirred at 100° C. for 10 hours. Thecatalyst in the reaction mixture was removed by filtration. The solventwas evaporated in vacuo. The residual solid was collected with hexaneand ethyl acetate (2/1 v/v) to give ethyl6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (104 mg). The mother liquidwas concentrated in vacuo, and the residue was purified by preparativethin layer column chromatography (hexane/ethyl acetate=2/1) to giveethyl 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (209 mg) as a paleyellow solid.

¹H-NMR (300 MHz, DMSO-d6) δ 1.28 (3H, t, J=7 Hz), 2.84 (2H, dd, J=16, 6Hz), 3.29 (2H, dd, J=16, 7 Hz), 4.24 (2H, q, J=7 Hz), 4.67 (1H, m), 6.52(1H, d, J=9 Hz), 7.11-7.19 (2H, m), 7.20-7.29 (2H, m), 7.72 (1H, d,J=6.5 Hz), 7.81 (1H, dd, J=9, 2.5 Hz), 8.60 (1H, d, J=2.5 Hz); MS (ES+)m/z 283.

Preparation 675

tert-Butyl[(1R)-1-{[(cyclohexylmethyl)amino]carbonyl)-3-(methylthio)propyl]carbamate(5.12 g) was dissolved in methyl iodide (23 mL) and stirred at roomtemperature for 18 hours. The excess methyl iodide was evaporated invacuo. The residue was dissolved in tetrahydrofuran (50 mL), addedlithium bis(trimethylsilyl)amide 1.0M solution in hexane (16.3 mL) at 0°C., and then allowed to warm to room temperature and stirred for 5hours. The resulting mixture was poured into aqueous ammonium chlorideand extracted with ethyl acetate. The organic phase was washed withbrine, dried over MgSO₄, concentrated in vacuo. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=from 80/20(v/v) to 60/40 (v/v)) to give tert-butyl[(3R)-1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]carbamate (2.0 g) as apale yellow solid.

¹H-NMR (300 MHz, CDCl₃) δ 0.86-1.04 (2H, m), 1.10-1.29 (3H, m), 1.45(3×3H, s), 1.51-1.91 (7H, m), 2.65 (1H, m), 3.03-3.41 (4H, m), 4.17 (1H,m), 5.14 (1H, m); MS (ES+) m/z 297.

Preparation 676

ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

To an ice-cooled solution of ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate(4.63 g) in dichloromethane (7.8 ml) were added anisole (4.7 ml) andtrifluoroacetic acid (15.6 ml), the mixture was stirred at 25° C. for3.5 hours. The mixed solution was poured into a mixture of water andAcOEt. The pH of the aqueous layer was adjusted to ca.8 with NaHCO₃. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and evaporated under reduced pressure to give crude powder. Theresulting residue was purified by column chromatography on silica gel(50 g) using a mixed solvent of CH₂Cl₂ and MeOH (100:1 to 20:1). Thefractions containing the objective compound were collected andevaporated under reduced pressure. Title compound (3.05 g, 85%) wasobtained as slightly yellowish powder.

MASS(API-ES); 353 (M+H),

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.50-1.80 (1H,m), 2.10-2.35 (1H, m), 2.36-2.55 (2H, m), 2.60-2.85 (2H, m), 3.50-3.66(2H, m), 4.16 (2H, a, J=7.1 Hz), 4.25-4.45 (1H, m), 6.49 (1H, d, J=15Hz), 7.15-7.40 (5H, m), 7.53 (1H, d, J=15 Hz), 7.93 (1H, d, J=6.6 Hz),8.00 (1H, s), 8.20 (1H, s).

The following compound was obtained in a similar manner to that ofPreparation 676.

Preparation 677

ethyl3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-2-fluoroacrylate(E,Z-Mixture)

MASS(API-ES); 371 (M+H)+,

¹H-NMR (200 MHz), (CDCl₃, δ): 1.20-1.50 (3H, m), 1.60-1.90 (1H, m),2.25-2.50 (2H, m), 2.60-2.80 (2H, m), 2.85-3.03 (1H, m), 3.67 (2H, s),4.33 (2H, q, J=7.2 Hz), 4.37-4.65 (1H, m), 5.24 (0.5H, d, J=7.6 Hz),5.37 (0.5H, d, J=7.6 Hz), 6.78 (0.5H, d, J=22 Hz), 6.98 (0.5H, d, J=37Hz), 7.20-7.40 (5H, m), 7.83 (0.5H, d, J=1.1 Hz), 7.89 (0.5H, d, J=1.1Hz), 8.47 (0.5H, d, J=1.1 Hz), 8.56 (0.5H, d, J=1.1 Hz).

Preparation 678

To a mixture of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylatedihydrochloride (256 mg) and cyclohexanone (64 mg) in 1,2-dichloroethane(5 mL) was added sodium triacetoxyborohydride (253 mg) andN,N-diisopropylethylamine (0.21 mL), and the mixture was stirred at roomtemperature for 2 hours. To the resultant was added saturated aqueousammonium chloride and ethyl acetate, and the mixture was stirred for 20min. The organic phase was separated, washed with brine and dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (chloroform/methanol=95/5 v/v) to giveethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(338 mg) as a pale yellow foam.

¹H-NMR (300 MHz, CDCl₃) δ 1.18-1.38 (4H, m), 1.35 (3H, t, J=7 Hz), 1.46(9H, s), 1.58-1.86 (5H, m), 2.06-2.35 (3H, m), 2.68 (1H, m), 2.95 (1H,m), 3.41 (1H, m), 3.65 (1H, m), 3.96 (1H, m), 4.28 (2H, q, J=7 Hz), 5.09(1H, m), 6.46 (1H, d, J=16 Hz), 7.30 (1H, d, J=9 Hz), 7.64 (1H, d, J=16Hz), 7.81 (1H, d, J=9 Hz), 8.48 (1H, s); MS (ES+) m/z 444.

The following compounds were obtained in a similar manner to that ofPreparation 678.

Preparation 679

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-cycloheptyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.21-1.72 (11H, m), 1.35 (3H, t, J=7 Hz), 1.45(9H, s), 1.73-1.88 (2H, m), 1.99 (1H, m), 2.18 (1H, m), 2.35 (1H, m),2.60 (1H, m), 2.75 (1H, m), 3.10 (1H, m), 4.28 (2H, q, J=7 Hz), 4.86(1H, m), 6.46 (1H, d, J=16 Hz), 7.31 (1H, d, J=8.5 Hz), 7.65 (1H, d,J=16 Hz), 7.81 (1H, d, J=8.5, 2.5 Hz), 8.54 (1H, d, J=2.5 Hz); MS (ES+)m/z 458.

Preparation 680

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.20-1.86 (8H, m), 1.35 (3H, t, J=7 Hz), 1.46(9H, s), 2.01 (1H, m), 2.21 (1H, m), 2.42-2.57 (2H, m), 2.63 (1H, m),2.83 (1H, m), 3.14 (1H, m), 4.28 (2H, q, J=7 Hz), 4.90 (1H, m), 6.46(1H, d, J=16 Hz), 7.32 (1H, d, J=8.5 Hz), 7.65 (1H, d, J=16 Hz), 7.81(1H, dd, J=8.5, 2 Hz), 8.54 (1H, d, J=2 Hz); MS (ES+) m/z 430.

Preparation 681

0.94 M solution of diisobutylaluminium hydride in hexane (2.73 ml) wasadded dropwise to a solution of ethyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinate (294 mg) inTHF (10 ml) with stirred below 5° C. under atmospheric pressure ofnitrogen, and the reaction mixture was stirred at the same temperaturefor 1.5 hrs. To the reaction mixture was added saturated aqueousammonium chloride (0.727 ml) below 5° C., then the mixture was stirredat 25° C. for 30 minutes. Na₂SO₄ (2.87 g) was added to the solution, andthe mixture was stirred at 25° C. for 15 minutes. The reaction mixturewas filtrated, the filtrate was evaporated in vacuo. Toluene (15 ml) wasadded to the residue, and the mixture was evaporated in vacuo. Theresulting residue and activated MnO₂ (744 mg) in ethyl, acetate (20 ml)were stirred at 75° C. for 1 hour. After removal of the insolublematerial by filtration, the filtrate was evaporated in vacuo to give6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg,98%) as syrup. The compound was used in the next step reaction withoutpurification.

Preparation 682

To an ice-cooled solution of ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl}acrylate(355 mg) in dichloromethane (2 ml) was added anisole (1.0 ml) andtrifluoroacetic acid (2.0 ml), the mixture was stirred at 25° C. for 1hour. The mixed solution was poured into a mixture of water and AcOEt.The pH of the aqueous layer was adjusted to ca.9 with NaHCO₃. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and evaporated under reduced pressure to give syrup. The residuewas dissolved in a mixed solvent of tetrahydrofuran (6 ml) and methanol(2.5 ml), and 1 mol/L-NaOH (1.5 mL) was added to the solution at 25° C.The mixture was stirred at 50° C. for 1.5 hours. The reaction mixturewas evaporated in vacuo, the resulting residue was poured into a mixtureof water and AcOEt. The pH of the aqueous layer was adjusted to ca.5with 1 mol/L hydrochloric acid. The organic layer was separated, driedover sodium sulfate and evaporated under reduced pressure to give(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (250 mg, 97%) as powder.

MASS(API-ES); 344 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.77 (10H, m), 1.78-2.47 (3H, m),3.10-3.90 (4H, m), 4.24-4.57 (1H, m), 6.25 (1H, d, J=16 Hz), 6.54 (1H,dd, J=2.2 Hz, J=8.8 Hz), 7.30-7.45 (1H, m), 7.46 (1H, d, J=16 Hz), 7.79(1H, d, J=8.8 Hz), 8.22 (1H, d, J=2.2 Hz).

Preparation 683

To a stirred solution of6-(2,3-dihydro-1H-inden-2-ylamino)nicotinaldehyde (160 mg) and malonicacid (84 mg) in pyridine (6 mL) was added piperidine (0.01 mL), and themixture was stirred at 100° C. for 2 hours. The solvent was evaporatedin vacuo and the resulting powder was collected by filtration to give(2E)-3-[6-(2,3-dihydro-1H-inden-2-ylamino)-3-pyridinyl]acrylic acid (190mg) as a pale yellow powder.

¹H-NMR (300 MHz, DMSO-d6) δ 2.83 (2H, dd, J=16, 6 Hz), 3.29 (2H, dd,J=16, 7 Hz), 4.64 (1H, m), 6.24 (1H, d, J=16 Hz), 6.52 (1H, d, J=9 Hz),7.10-7.29 (4H, m), 7.4-7.52 (2H, m), 7.77 (1H, dd, J=9, 2.2 Hz), 8.23(1H, d, J=2.2 Hz), 12.06 (1H, br); MS (ES+) m/z 281.

The following compounds were obtained in a similar manner to that ofPreparation 683.

Preparation 684

(2E)-3-(6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro-3-pyridinyl}acrylicacid

¹H-NMR (300 MHz, CDCl₃) δ 1.50 (1H, m), 1.68-2.06 (4H, m), 2.33 (1H, m),3.87 (1H, m), 4.49 (1H, m), 4.67 (2H, s), 5.21 (1H, d, J=7 Hz), 6.23(1H, d, J=16 Hz), 7.23-7.38 (5H, m), 7.65 (1H, d, J=16 Hz), 7.68 (1H, d,J=1.8 Hz), 8.18 (1H, d, J=1.8 Hz); MS (ES+) m/z 373.

Preparation 685

(2E)-3-(5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, CDCl₃) δ 1.26 (1H, m), 1.40 (1H, m), 2.14 (1H, ddd,J=9, 6, 3 Hz), 3.09 (1H, m), 5.65 (1H, d, J=3 Hz), 6.25 (1H, d, J=15.7Hz), 7.17-7.36 (5H, m), 7.64 (1H, d, J=15.7 Hz), 7.70 (1H, d, J=2 Hz),8.24 (1H, d, J=2 Hz); MS (ES+) m/z 315.

Preparation 686

(2E)-3-{6-[(2-benzylphenyl)amino]-5-chloro-3-pyridinyl}acrylic acid

¹H-NMR (300 MHz, DMSO-d6) δ 3.92 (2H, s), 6.44 (1H, br), 7.07-7.30 (8H,m), 7.39 (1H, br), 7.45 (1H, d, J=8 Hz), 8.08-8.25 (3H, m); MS (ES+) m/z365.

Preparation 687

(2E)-3-[5-chloro-6-({2-[(cyclohexylcarbonyl)amino]phenyl}amino)-3-pyridinyl]acrylicacid

¹H-NMR (300 MHz, DMSO-d6) δ 1.10-1.86 (10H, m), 2.41 (1H, m), 6.49 (1H,d, J=16 Hz), 7.11-7.30 (3H, m), 7.48 (1H, d, J=16 Hz), 7.77 (1H, d,J=7.5 Hz), 8.24 (1H, d, J=1 Hz), 8.26 (1H, d, J=1 Hz), 8.36 (1H, s),9.93 (1H, s), 12.28 (1H, br-s); MS (ES+) m/z 400.

Preparation 688

(2E)-3-[5-chloro-6-({3-[(cyclohexylcarbonyl)amino]phenyl}amino)-3-pyridinyl]acrylicacid

¹H-NMR (300 MHz, DMSO-d6) δ 1.13-1.48 (5H, m), 1.58-1.84 (5H, m), 2.33(1H, m), 6.51 (1H, d, J=16 Hz), 7.16-7.34 (3H, m), 7.52 (1H, d, J=16Hz), 7.95 (1H, s), 8.25 (1H, d, J=2 Hz), 8.33 (1H, d, J=2 Hz), 8.70 (1H,s), 9.80 (1H, s); MS (ES+) m/z 400.

Preparation 689

A mixture of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (2.0 g),trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexanecarboxylate (1.68g), HOBt (880 mg) and WSCD (1.26 g) in dichloromethane (40 ml) and Et₃N(1.51 ml) (2.0 eq) was stirred at room temperature for 8 hours.

After then, water was added and the reaction mixture was extracted withdichloromethane (twice).

Combined organic layer was washed with water (twice) and brine, driedover MgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel to give 2.85 g (98%) ofethyl(2E)-3-[6-({(3R)-1-[(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-pyrrolidinyl}amino)-5-chloro-3-pyridinyl]acrylate.

MASS (ESI+): m/z=557.2 (M+Na).

¹HNMR (400 MHz, CDCl₃): δ 0.8-2.4 (12H, m), 1.43 and 1.44 (9H, s), 1.33(3H, t, J=7.1 Hz), 2.8-4 (6H, m), 4.24 (1H, t, J=7.1 Hz), 4.25 (1H, t,J=7.1 Hz), 4.53-4.8 (2H, m), 5.26 (1H, dd, J=6.4, 20 Hz), 6.25 (1H, dd,J=6.6, 16 Hz), 7.54 (1H, dd, J 4.6, 16 Hz), 7.69 (1H, dd, J=2, 7.9 Hz),8.15 (1H, dd, J=2, 7.6 Hz).

Preparation 690

4NHCl/Dioxane (14 ml) was added to ethyl(2E)-3-[6-({(3R)-1-[(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-pyrrolidinyl}amino)-5-chloro-3-pyridinyl]acrylate(3.0 g) under ice cooling.

After 2 hours, IPE was added to this reaction mixture.

The mixture was decantated and dioxane and IPE was separated.

Residue was evaporated under reduced pressure to give 2.80 g (98%) ofethyl(2E)-3-{6-[((3R)-1-{[trans-4-(aminomethyl)cyclohexyl]carbonyl}-3-pyrrolidinyl)amino]-5-chloro-3-pyridinyl}acrylatedihydrochloride as an amorphous.

MASS (ESI+): m/z=435.2 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 0.90-2.80 (12H, m), 1.24 (3H, t, J=7.1 Hz),2.94-3.88 (6H, m), 4.16 (2H, q, J=7.1 Hz), 4.54 and 4.68 (1H, br.s),6.53 (1H, dd, J=3.2, 15.9 Hz), 7.54 (1H, dd, J=2.6, 15.9 Hz), 7.9-8.02(2H, m), 8.17 (1H, dd, J=1.9, 5.8 Hz), 8.33 (1H, dd, J=1.9, 4.8 Hz).

Preparation 691

A mixture of ethyl(2E)-3-{6-[((3R)-1-{[trans-4-(aminomethyl)cyclohexyl]carbonyl}-3-pyrrolidinyl)amino]-5-chloro-3-pyridinyl}acrylatedihydrochloride (1.0 g), Formaldehyde (1.0 ml), NaBH(OAc)₃ (1.25 g) andtriethylamine (2.0 eq. 398 mg, 0.55 ml) in dichloromethane (20 ml) wasstirred at room temperature for 8 hours.

After then, water was added and the reaction mixture was extracted withdichloromethane (twice).

Combined organic layer was washed with sat. sodium bicarbonate andwater, and dried over MgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel to give 660 mg (72%) ofethyl(2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl)carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl}acrylate.

MASS (ESI+): m/z=463.3 (M+1).

¹HNMR (400 MHz): δ 0.80-2.45 (14H, m), 1.33 (3H, t, J=7.2 Hz), 1.33 (3H,t, J=7.1 Hz), 2.23 and 2.24 (6H, s), 3.36-4.01 (4H, m), 4.25 (1H, q,J=7.2 Hz), 4.26 (1H, q, J=7.1 Hz), 4.6-4.75 (1H, m), 5.26 (1H, dd,J=6.5, 21.2 Hz), 6.25 (1H, dd, J=6, 15.9 Hz), 7.54 (1H, dd, J=4, 15.9Hz), 7.69 (1H, dd, J=2, 7.7 Hz), 8.15 (1H, dd, J=2, 6.3 Hz).

Preparation 692

A mixture of I (610 mg) and 1NNaOH (5 ml) in THF (20 ml) and MeOH (20ml) was stirred at 60° C. for 3 hrs.

1N HCl (5 ml) was added.

The mixture was evaporated under reduced pressure.

Toluene was added and evaporated again to give 600 mg (quant.) of(2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl)carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl}acrylicacid.

This product was used for next transformation.

MASS (ESI−): m/z=433.3 (M−1).

Preparation 693

A mixture of(2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl)carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl}acrylicacid (600 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (194 mg), HOBt(242 mg) and WSCD (321 mg) in DMF (40 ml) was stirred at roomtemperature for 8 hours.

After then, water was added and the reaction mixture was extracted withdichloromethane (twice).

Combined organic layer was washed with water (twice) and brine, driedover MgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel to give 530 mg (72%) of(2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl)carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide.

MASS (ESI+): m/z=534.2 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 0.82-2.44 (20H, m), 2.23 and 2.24 (6H, s),3.32-4.05 (6H, m), 4.60-4.75 (1H, m), 5.01 (1H, br.s), 5.23 (1H, dd,J=6.5, 20.6 Hz), 7.56 (1H, d, J=5.2 Hz), 7.6 (1H, d, J=5.2 Hz), 7.66(1H, d, J=8.8 Hz), 8.16 (H, d, J=8.8 Hz).

Preparation 694

A diisobutylaluminium hydride in toluene solution (4.6 mL) was dropwiseadded to a solution of ethyl ethyl5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}nicotinate (488 mg) intetrahydrofuran (15 mL) with stirring at 0° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at 0° C. for1 hour. A methanol (1 mL) was added to a reaction mixture at 0° C. andallowed to warm to room temperature. Tetrahydrofuran (20 mL) andsaturated sodium potassium tartarate aqueous solution (5 mL) was addedand the resultant mixture was stirred at ambient temperature for 1 hour.The reaction mixture was filtrated and the filtrate was dried overMgSO₄. The solvent was evaporated in vacuo and the residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=2:1 v/v) togive(5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}-3-pyridinyl)methanol(398 mg).

¹H-NMR (300 MHz, CDCl₃) δ 1.24 (1H, m), 1.37 (1H, m), 1.62 (1H, t, J=5Hz), 2.10 (1H, m), 3.03 (1H, m), 4.56 (1H, d, J=5 Hz), 5.37 (1H, s),7.16-7.34 (6H, m), 7.54 (1H, d, 3=2 Hz), 8.07 (1H, d, J=2 Hz); MS (ES+)m/z 275.

The following compounds were obtained in a similar manner to that ofPreparation 694.

Preparation 695

N-(2-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}phenyl)cyclohexanecarboxamide

¹H-NMR (300 MHz, CDCl₃) δ 1.18-1.38 (3H, m), 1.42-1.59 (2H, m), 1.68(1H, m), 1.74-1.97 (4H, m), 2.28 (1H, m), 3.68 (1H, t, J=5.5 Hz), 4.54(2H, d, J=5.5 Hz), 7.13 (1H, ddd, J=7.7, 7.7, 1.5 Hz), 7.21 (1H, ddd,J=7.7, 7.7, 1.5 Hz), 7.44 (1H, dd, J=7.7, 1.5 Hz), 7.48 (1H, s),7.65-7.72 (2H, m), 7.99 (1H, d, J=1.8 Hz), 8.37 (1H, s); MS (ES+) m/z360.

Preparation 696

{6-[(2-benzylphenyl)amino]-5-chloro-3-pyridinyl)methanol

¹H-NMR (300 MHz, CDCl₃) δ 1.60 (1H, t, J=5.5 Hz), 4.03 (2H, s), 4.56(2H, d, J=5.5 Hz), 6.65 (1H, s), 7.08-7.36 (8H, m), 7.59 (1H, d, J=2Hz), 7.92 (1H, d, J=8 Hz), 8.02 (1H, d, J=2 Hz); MS (ES+) m/z 325.

Preparation 697

A mixture of ethyl(2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride (600 mg), cyclohexylacetic acid (255 mg), HOBt (264 mg)and WSCD (379 mg) in dichlroromethane (20 ml) was stirred at roomtemperature for 8 hours.

After then, water was added and the reaction mixture was extracted withdichloromethane (twice).

Combined organic layer was washed with water (twice) and brine, driedover MgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel to give 630 mg (92%) ofethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate.

MASS (ESI+): m/z=442.3 (M+Na).

¹HNMR (400 MHz, CDCl₃): δ 0.85-1.38 (3H, m), 1.33 (3H, t, J=7.1 Hz),1.6-2.4 (12H, m), 3.35-3.95 (4H, m), 4.25 (1H, q, J=7.1 Hz), 4.26 (1H,q, J=7.1 Hz), 4.61-4.75 (1H, m), 5.26 (1H, dd, J=6.4, 15.5 Hz), 6.25(1H, dd, J=5.2, 16 Hz), 7.54 (1H, dd, J=3.3, 15.9 Hz), 7.69 (1H, dd,J=2.1, 6.4 Hz), 8.15 (1H, dd, J=2, 4.7 Hz).

Preparation 698

A mixture of ethyl(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate(600 mg) and 1N NaOH (6 ml) in THF (20 ml) and MeOH (20 ml) was stirredat 50° C. for 2 hrs. 1N HCl (6 ml) was added.

Evaporated under reduced pressure.

Added toluene and evaporated to give 550 mg of crude(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid.

This product was used for next transformation.

MASS (ESI−): m/z=390.2 (M−1).

Preparation 699

ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinate

To a solution of ethyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate (500mg) in ethanol (20 mL) were added ammonium formate (584 mg) and 10% Pd/C(300 mg) at 25° C. and the mixture was heated to reflux with stirringfor 1 hour. After cooling, the catalyst in the reaction mixture wasremoved by filtration. The filtrate was evaporated in vacuo. To theresidue were added CH₂Cl₂ (30 ml), ethanol (7 mL), and benzaldehyde (140mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride(280 mg) was added to the mixture. The reaction mixture was stirred at25° C. for 3 hours, and then poured into a mixture of CH₂Cl₂ and aqueousNaHCO₃. The organic layer was separated, dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (11 g) using a mixed solvent of dichloromethane and MeOH(100:1 to 40:1). The fractions containing the objective compound werecollected and evaporated under reduced pressure. Title compound (302 mg,66%) was obtained as colorless syrup.

MASS(API-ES); 344 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.28 (3H, t, J=7.1 Hz), 1.70-1.95 (1H,m), 2.05-2.30 (1H, m), 2.35-2.70 (3H, m), 2.80-2.90 (1H, m), 3.58 (2H,s), 4.24 (2H, q, J=7.1 Hz), 4.40-4.60 (1H, m), 7.15-7.35 (5H, m), 7.54(1H, d, J=6.3 Hz), 7.64 (1H, dd, J=1.9 Hz, J=12 Hz), 8.41 (1H, d, J=1.9Hz).

Preparation 700

A mixture of m-phenylenediamine (2.00 g), cyclohexanecarboxylic acid(2.37 g), HOBt (2.75 g) and EDCI (3.9 g) in DMF (20 mL) was stirred atambient temperature for 2 hours. The reaction mixture was diluted withwater and the resulting solid was collected by filtration. The solid waspurified by silica gel column chromatography (hexane/ethyl acetate=4/1to 1/2 v/v) to give N-(3-aminophenyl)cyclohexanecarboxamide (2.2 g) as awhite powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.20-1.39 (3H, m), 1.44-1.62 (2H, m), 1.70(1H, m), 1.77-2.00 (4H, m), 2.20 (1H, m), 3.68 (2H, s), 6.42 (1H, dd,J=8, 2 Hz), 6.64 (1H, dd, J=8, 2 Hz), 7.06 (1H, dd, J=8, 8 Hz), 7.07(1H, br), 7.23 (1H, s); MS (ES+) m/z 219.

The following compound was obtained in a similar manner to that ofPreparation 700.

Preparation 701

N-(2-aminophenyl)cyclohexanecarboxamide

¹H-NMR (300 MHz, CDCl₃) δ 1.20-2.06 (10H, m), 2.31 (1H, m), 3.83 (2H,br-s), 6.74-6.86 (2H, m), 7.05 (1H, m), 7.10-7.23 (2H, m); MS (ES+) m/z219.

Preparation 702

ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate

0.94 M solution of diisobutylaluminium hydride in hexane (4.82 ml) wasadded dropwise to a solution of methyl5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate(1.01 g) in THF (20 ml) with stirred below −60° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at −55 to−50° C. for 1 hr. To the reaction mixture was added saturated aqueousammonium chloride (1.28 ml) at the same temperature, then the mixturewas stirred at 25° C. for 40 minutes. THF (14 ml) and MgSO₄ (4.36 G)were added to the solution, and the mixture was stirred at 25° C. for 15minutes. The reaction mixture was filtered, and then to the filtrate wasadded ETHYL (triphenylphosphoranylidene)acetate (1.07 g), and themixture was stirred at 25° C. for 16 hr. The reaction mixture was pouredinto a mixture of AcOEt and 5% aqueous NaCl. The separated organic layerwas washed with brine, dried over sodium sulfate and evaporated invacuo. The resulting residue was purified by column chromatography onsilica gel (51 g) using a mixed solvent of hexane and ethyl acetate (7:2to 2:1). The fractions containing the objective compound were collectedand evaporated under reduced pressure. Title compound (584 mg, 53%) wasobtained as slightly yellowish oil.

MASS(API-ES); 453 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.21-1.42 (13H, m), 1.88-2.30 (2H, m),2.35-2.77 (3H, m), 3.42, 3.51 (2H, ABq, J=13 Hz), 4.24 (2H, q, J=7.1Hz), 4.66-4.88 (1H, m), 6.94 (1H, d, J=16 Hz), 7.03-7.33 (5H, m), 7.76(1H, d, J=16 Hz), 8.67 (1H, d, J=1.0 Hz), 8.80 (1H, d, J=1.0 Hz).

Preparation 703

Palladium(II) acetate (75 mg) and2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (313 mg) in dioxane (5mL) was stirred at ambient temperature for 15 minutes. To thissuspension was added 2,6-dichloropyrazine (1.00 g),(3R)-(−)-1-benzyl-3-aminopyrrolidine (1.42 g), and cesium carbonate(3.28 g), and the mixture was heated at 80 C for 8 hours. The resultingmixture was allowed to cool to ambient temperature, poured into water,and extracted with ethyl acetate. The organic phase was washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography(chloroform/methanol=96/4 v/v) to giveN-[(3R)-1-benzyl-3-pyrrolidinyl]-6-chloro-2-pyrazinamine (1.00 g) as ayellow solid.

¹H-NMR (300 MHz, CDCl₃) δ 1.67 (1H, m), 2.30-2.44 (2H, m), 2.64 (1H, dd,J=10, 4 Hz), 2.68 (1H, dd, J=10, 5.5 Hz), 2.89 (1H, m), 3.62 (1H, d,J=13 Hz), 3.66 (1H, d, J=13 Hz), 4.38 (1H, m), 5.09 (1H, d, J=8 Hz),7.22-7.38 (5H, m), 7.71 (1H, s), 7.77 (1H, s); MS (ES+) m/z 289.

The following compounds were obtained in a similar manner to that ofPreparation 703.

Preparation 704

ethyl (2E)-3-(5-{[2-(1-piperidinyl)phenyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7 Hz), 1.63 (2H, m), 1.69-1.80(4H, m), 2.79-2.88 (4H, m), 4.27 (2H, q, J=7 Hz), 6.78 (1H, d, J=15.5Hz), 7.04 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.11-7.20 (2H, m), 7.63 (1H, d,J=15.5 Hz), 8.19-8.24 (3H, m), 8.28 (1H, dd, J=7.5, 1.5 Hz); MS (ES+)m/z 353.

Preparation 705

ethyl(2E)-3-[4-({2-[(cyclohexylcarbonyl)amino]phenyl}amino)phenyl]acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.18-1.38 (5H, m), 1.33 (3H, t, J=7 Hz), 1.42(1H, m), 1.65 (1H, m), 1.72-1.91 (4H, m), 2.20 (1H, m), 4.24 (2H, q, J=7Hz), 6.08 (1H, s), 6.27 (1H, d, J=15.7. Hz), 6.75 (2H, d, J=8.5 Hz),7.12-7.22 (2H, m), 7.31 (1H, m), 7.38 (2H, d, J=8.5 Hz), 7.53 (1H, s),7.61 (1H, d, J=15.7 Hz), 7.82 (1H, m); MS (ES+) m/z 393.

Preparation 706

ethyl3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)-2-fluoroacrylate(E,Z-Mixture)

0.94 M solution of diisobutylaluminium hydride in hexane (5.79 ml) wasadded dropwise to a solution of methyl5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate(1.18 g) in THF (25 ml) with stirred below −60° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at −55 to−50° C. for 1 hr. To the reaction mixture was added saturated aqueousammonium chloride (1.54 ml) at the same temperature, then the mixturewas stirred at 25° C. for 40 minutes. THF (15 ml), MgSO₄ (7 G) andNa₂SO₄ (15 g) were added to the solution, and the mixture was stirred at25° C. for 15 minutes. The reaction mixture was filtered, the filtratewas Filtrate (A). On the other hand, to an ice-cooled solution of ethyl(diethoxyphosphoryl)(fluoro)acetate (970 mg) in THF (21 ml) was addedMgBr₂ (885 mg), and triethylamine (0.614 ml), then the mixture wasstirred at 50° C. for 2 hours. The reaction mixture was poured into amixture of AcOEt and 5% aqueous NaCl. The separated organic layer waswashed with brine, dried over sodium sulfate and evaporated in vacuo.The resulting residue was purified by column chromatography on silicagel (20 g) using a mixed solvent of hexane and ethyl acetate (2:1 to1:1). The fractions containing the objective compound were collected andevaporated under reduced pressure. Title compound (674 mg, 50%) wasobtained as oil.

MASS(API-ES); 471 (M+H)+

Preparation 707

A mixture of N-[(3R)-1-benzyl-3-pyrrolidinyl]-6-chloro-2-pyrazinamine(980 mg), di-tert-butyl dicarbonate (1.48 g) and 4-dimethylaminopyridine(83 mg) in acetonitrile (20 mL) was stirred at 100° C. for 3 days. Thereaction mixture was poured into brine and extracted with ethyl acetate.The organic phase was washed with aqueous ammonium chloride, aqueoussodium hydrogen carbonate, and brine, dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=75/25) to give tert-butyl[(3R)-1-benzyl-3-pyrrolidinyl](6-chloro-2-pyrazinyl)carbamate (925 mg)as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.90-2.11 (2H, m), 2.26 (1H, m),2.58-2.78 (3H, m), 2.88 (1H, m), 3.53 (1H, d, J=13 Hz), 3.62 (1H, d,J=13 Hz), 4.92 (1H, m), 7.17-7.36 (5H, m), 8.35 (1H, s), 8.51 (1H, s);

MS (ES+) m/z 389.

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 708

tert-butyl[(3R)-1-cyclopentyl-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 1.20-1.78 (14H, m), 1.38 (9H, s), 1.82-2.15(2H, m), 2.20-2.53 (4H, m), 3.54 (1H, m), 3.96 (1H, m), 4.72 (1H, m),4.92 (1H, m), 6.58 (1H, d, 3=16 Hz), 7.36 (1H, d, J=7 Hz), 7.53 (1H, d,J=16 Hz), 8.01 (1H, dd, J=7, 2 Hz), 8.63 (1H, d, J=2 Hz), 11.32 (1H,br-s); MS (ES+) m/z 501.

Preparation 709

To a stirred solution of 1-(bromomethyl)-2-nitrobenzene (2.10 g) in DMF(20 mL) was added pyrrolidine (0.95 mL) and N,N-diisopropylethylamine(2.54 mL), and the mixture was stirred at 60° C. for 24 hours. Theresulting mixture was poured into ethyl acetate and brine. The organicphase was separated and washed with brine, dried over sodium sulfate.The solvent was evaporated in vacuo and the residue was purified bysilica gel column chromatography to give 1-(2-nitrobenzyl)pyrrolidine(1.92 g) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 1.71-1.83 (4H, m), 2.46-2.57 (4H, m), 3.93(2H, s), 7.37 (1H, ddd, J=8, 7.5, 1.5 Hz), 7.55 (1H, ddd, J=8, 7.5, 1.5Hz), 7.69 (1H, br-d, J=8 Hz), 7.85 (1H, dd, J=8, 1.5 Hz); MS (ES−) m/z205.

Preparation 710

A mixture of(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid (550 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (198 mg), HOBt(247 mg) and WSCD (218 mg) in DMF (40 ml) was stirred at roomtemperature for 8 hours.

After then, water was added and the reaction mixture was extracted withdichloromethane (twice).

Combined organic layer was washed with water (twice) and brine, driedover MgSO₄, filtered and evaporated.

Residue was column chromatographed on silica gel to give 680 mg (99%) of(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide.

MASS (ESI+): m/z=513.3 (M+Na).

¹HNMR (400 MHz, CDCl₃): δ 0.85-1.35 (5H, m), 1.55-2.41 (15H, m),3.35-4.05 (6H, m), 4.60-4.73 (1H, m), 4.99 (1H, br.s), 5.19-5.28 (1H,m), 4.61-4.75 (1H, m), 7.56-7.70 (2H, m), 8.02 (1H, s), 8.16 (1H, s),8.48-8.52 (1H, m).

Preparation 711

ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl}acrylate

To an ice-cooled suspension of sodium hydride (38.5 mg) in THF (10 ml)was added ethyl (diethoxyphosphoryl)acetate (206 mg), and the mixturewas stirred at 24° C. for 40 minutes. To the mixture was added6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg)at 24° C., the reaction mixture was stirred at same temperature for 30minutes. The reaction mixture was poured into a mixture of AcOEt and 5%aqueous NaCl. The separated organic layer was washed with brine, driedover sodium sulfate and evaporated in vacuo. The resulting residue waspurified by column chromatography on silica gel (8.2 g) using a mixedsolvent of CH₂Cl₂ and MeOH (100:1 to 35:1). The fractions containing theobjective compound were collected and evaporated under reduced pressure.Title compound (111 mg, 36%) was obtained as oil.

MASS(API-ES); 370 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.0 Hz), 1.45-2.70 (5H,m), 2.80-2.90 (1H, m), 3.57 (2H, s), 4.15 (2H, q, 0.3=7.0 Hz), 4.35-4.60(1H; m); 6.41 (1H, d, J=16 Hz), 7.15-7.40 (6H, m), 7.53 (1H, d, J=16Hz), 7.84 (1H, dd, J=1.1 Hz, J=13 Hz), 8.08 (1H, d, J=1.1 Hz).

Preparation 712

ethyl(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate

0.94 M solution of diisobutylaluminium hydride in hexane (38.3 ml) wasadded dropwise to a solution of methyl5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate(8.42 g) in THF (170 ml) with stirred below −60° C. under atmosphericpressure of nitrogen, and the reaction mixture was stirred at −55 to−50° C. for 1 hr. To the reaction mixture was added saturated aqueousammonium chloride (10.2 ml) at the same temperature, then the mixturewas stirred at 25° C. for 40 minutes. THF (60 ml) and MgSO₄ (34.1 G)were added to the solution, and the mixture was stirred at 25° C. for 15minutes. The reaction mixture was filtrated, the filtrate was Filtrate(A). On the other hand, to an ice-cooled suspension of sodium hydride(938 mg) in THF (90 ml) was added ethyl (diethoxyphosphoryl)acetate(5.26 g), and the mixture was stirred at 25° C. for 1 hr. To the mixturewas added Filtrate (A) at 25° C., the reaction mixture was stirred atsame temperature for 30 minutes. The reaction mixture was poured into amixture of AcOEt and 5% aqueous NaCl. The separated organic layer waswashed with brine, dried over sodium sulfate and evaporated in vacuo.The resulting residue was purified by column chromatography on silicagel (116 g) using a mixed solvent of hexane and ethyl acetate (5:1 to1:1). The fractions containing the objective compound were collected andevaporated under reduced pressure. Title compound (6.74 g, 73%), wasobtained as slightly yellowish oil.

MASS(API-ES); 453 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.24-1.45 (13H, m), 1.90-2.30 (2H, m),2.35-2.80 (3H, m), 3.42, 3.51 (2H, ABq, J=13 Hz), 4.24 (2H, q, J=7.1Hz), 4.65-4.90 (1H, m), 6.94 (1H, d, J=16 Hz), 7.00-7.30 (5H, m), 7.76(1H, d, J=16 Hz), 8.67 (1H, d, J=1.0 Hz), 8.80 (1H, d, J=1.0 Hz).

Preparation 713

ethyl6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-fluoronicotinate

To a solution of ethyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate(1.43 g) in ethanol (30 mL) were added ammonium formate (1.67 g) and 10%Pd/C (600 mg) at 25° C. and the mixture was heated to reflux withstirring for 30 minutes. After cooling, the catalyst in the reactionmixture was removed by filtration. The filtrate was evaporated in vacuo.To the residue were added CH₂Cl₂ (15 ml), ethanol (3 mL), di-tert-butyldicarbonate (830 mg), and N,N-diisopropylethylamine (0.66 ml) at 25° C.After stirring for 5 minutes, sodium triacetoxyborohydride (280 mg) wasadded to the mixture. The reaction mixture was stirred at 25° C. for 2hours, and then evaporated under reduced pressure. The residue waspoured into a mixture of ethyl acetate, THF and water. The organic layerwas separated, washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (34 g) using a mixed solvent of hexane and ethyl acetate(4:1 to 3:1). The fractions containing the objective compound werecollected and evaporated under reduced pressure. Title compound (1.088g, 81%) was obtained as colorless syrup.

MASS(API-ES); 354 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.29 (3H, t, J=7.1 Hz), 1.39 (9H, s),1.80-2.30 (2H, m), 3.10-3.70 (4H, m), 4.26 (2H, q, J=7.1 Hz), 4.45-4.65(1H, m), 7.67 (1H, d, J=6.8 Hz), 7.69 (1H, dd, J=1.7 Hz, J=12 Hz), 8.46(1H, d, J=1.7 Hz).

Preparation 714

tert-butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-3-fluoro-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

Tert-butyl(3R)-3-{[3-fluoro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate(990 mg) and activated MnO₂ (2.76 g) in ethyl acetate (20 ml) werestirred at 75° C. for 1 hour. After removal of the insoluble material byfiltration, the filtrate was evaporated in vacuo to give syrup (A). Onthe other hand, to an ice-cooled suspension of sodium hydride (159 mg)in THF (20 ml) was added ethyl (diethoxyphosphoryl)acetate (855 mg), andthe mixture was stirred at 24° C. for 60 minutes. To the mixture wasadded syrup (A) at 24° C., the reaction mixture was stirred at sametemperature for 30 minutes. The reaction mixture was poured into amixture of AcOEt and 5% aqueous NaCl. The separated organic layer waswashed with brine, dried over sodium sulfate and evaporated in vacuo.The resulting residue was purified by column chromatography on silicagel (19 g) using a mixed solvent of hexane and ethyl acetate (5:1 to3:2). The fractions containing the objective compound were collected andevaporated under reduced pressure. Title compound (1.09 g, 90%) wasobtained as colorless oil.

MASS(API-ES); 380 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.39 (9H, s),1.80-2.30 (2H, m), 3.10-3.70 (4H, m), 4.16 (2H, q, J=7.1 Hz), 4.35-4.65(1H, m), 6.46 (1H, d, J=16 Hz), 7.42 (1H, d, J=5.9 Hz), 7.56 (1H, dd,J=1.8 Hz, J=16 Hz), 7.89 (1H, dd, J=1.5 Hz, J=13 Hz), 8.14 (1H, d, J=1.5Hz).

Preparation 715

To a stirred solution of tert-butyl[(3R)-1-benzyl-3-pyrrolidinyl](6-chloro-2-pyrazinyl)carbamate (910 mg)in DMF (15 mL) was added ethyl acrylate (1.27 mL), palladium(II) acetate(26 mg), tris(2-methylphenyl)phosphine (107 mg), andN,N-diisopropylethylamine (1.22 mL). The mixture was stirred in thesealed tube at 150° C. for 3 days. The resulting mixture was allowed tocool to ambient temperature, poured into water, and extracted with ethylacetate. The organic phase was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with a mixture of chloroform and methanol (96:4v/v) to give ethyl(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate(755 mg) as a pale yellow foam.

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.45 (9H, s), 2.12 (1H,m), 2.27 (1H, m), 2.58-2.70 (2H, m), 2.77 (1H, dd, J=9, 7 Hz), 2.94 (1H,dd, J=9, 8 Hz), 3.54 (1H, d, J=13 Hz), 3.63 (1H, d, J=13 Hz), 4.30 (2H,q, J=7 Hz), 4.95 (1H, m), 6.96 (1H, d, J=15.5 Hz), 7.04-7.49 (5H, m),7.64 (1H, d, J=15.5 Hz), 8.38 (1H, s), 8.54 (1H, s); MS (ES+) m/z 453.

Preparation 716

A mixture of (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylthio)butanoicacid (4.57 g), cyclohexanemethylamine (2.28 g), HOBt (2.72 g), and EDCI(3.87 g) in DMF (50 mL) was stirred at ambient temperature for 15 hours.The reaction mixture was poured into a mixture of AcOEt-H₂O and theorganic layer was washed with aqueous ammonium chloride, aqueous sodiumhydrogen carbonate, and brine and dried over MgSO₄. The solvent wasevaporated in vacuo and the residue was crystallized from ethyl acetateand hexane to give tert-butyl[(1R)-1-{[(cyclohexylmethyl)amino]carbonyl}-3-(methylthio)propyl]carbamate(5.65 g).

¹H-NMR (300 MHz, CDCl₃) δ 0.84-1.00 (2H, m), 1.08-1.32 (3H, m), 1.45(3×3H, s), 1.45 (1H, m), 1.60-1.77 (5H, m), 1.92 (1H, m), 2.09 (1H, m),2.11 (3H, s), 2.45-2.65 (2H, m), 3.02-3.18 (2H, m), 4.21 (1H, m), 5.14(1H, m), 6.22 (1H, br-t, J=6 Hz); MS (ES+) m/z 345.

Preparation 717

1) A solution of methyl 5-chloro-2-pyrazinecarboxylate (10 g) in THF(100 ml) was cooled under −5° C. by NaCl-ice bath.

To this solution was added dropwise DIBAL (60 ml) for 15 min under −8−0°C.

After stirring for 30 min under 0° C., the reaction mixture was quenchedwith EtOH (17 ml).

2) To a solution of ethyl (diethoxyphosphoryl)acetate (14.2 g) in THF(100 ml) was added portionwise NaH under ice-cooling.

The reaction mixture was allowed stirred at 30° C. for 1 hr.

To a solution of 1) was added dropwise 2) under 0° C.

After stirring for 1 hr, the reaction mixture was added to water andEtOAc, adjusted pH at 3.0.

Aqueous layer was separated and extracted twice with EtOAc, washed withwater, dried over MgSO₄, filtered and evaporated.

The residue was column chromatographed on silica gel (Yamazen HPLC).

Desired Fraction was evaporated and hexane was added.

Crystal was filtered and dried to give 3.15 g of ethyl(2E)-3-(5-chloro-2-pyrazinyl)acrylate.

Combined unpure fractions was chromatographed to give additional 1.6 gof ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate.

¹HNMR (400 MHz, CDCl₃): δ 1.35 (3H, t, J=7.1 Hz), 4.30 (2H, q, J=7.1Hz), 7.00 (1H, d, J=15.7 Hz), 7.66 (1H, d, J=15.7 Hz), 8.43 (1H, d,J=1.3 Hz), 8.60 (1H, d, J=1.3 Hz).

Preparation 718

To an ice-cooled solution of tert-butyl(3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-3-fluoro-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(11.6 g) in EtOH (70 ml) was added solution of 4N HCl in dioxane (76.4ml). The mixture was stirred at 24° C. for 3.5 hr, and evaporated underreduced pressure. The residue was poured into a mixture of water andCH₂Cl₂. The pH of the aqueous layer was adjusted to ca.9 with NaHCO₃.The organic layer was separated, dried over sodium sulfate andevaporated under reduced pressure to give ethyl(2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (7.1g, 83%) as colorless powder.

MASS(API-ES); 280 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.50-2.20 (2H,m), 2.60-3.03 (4H, m), 3.18 (1H, br), 4.16 (2H, q, J=7.1 Hz), 4.30-4.50(1H, m), 6.42 (1H, d, J=16 Hz), 7.19 (1H, d, J=6.4 Hz), 7.55 (1H, dd,J=2.0 Hz, J=16 Hz), 7.84 (1H, dd, J=1.8 Hz, J=13 Hz), 8.11 (1H, d, J=1.8Hz).

Preparation 719

ethyl(2E)-3-[5-fluoro-6-({(3R)-1-[2-(1H-pyrazol-1-yl)ethyl]-3-pyrrolidinyl}amino)-3-pyridinyl}acrylate

To a mixed solution of 1-(2,2-dimethoxyethyl)-1H-pyrazole (705 mg) indioxane (3 mL) and water (3 ml) were added 4N-HCl in 1,4-dioxanesolution (3.01 ml) at 25° C. and the mixture was heated at 60° C. withstirring for 40 minutes. After cooling, to the reaction mixture wasadded ethyl acetate, THF, and water. The pH of the aqueous layer wasadjusted to ca.3 with NaHCO₃. The organic layer was separated, driedover sodium sulfate and evaporated under reduced pressure. To theresulting residue were added CH₂Cl₂ (6 ml), ethyl(2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (420mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride(637 mg) was added to the mixture. The reaction mixture was stirred at25° C. for 5 hours, and then poured into a mixture of CH₂Cl₂ and aqueousNaHCO₃. The organic layer was separated, dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using a mixed solvent of dichloromethane and MeOH (60:1 to20:1). The fractions containing the objective compound were collectedand evaporated under reduced pressure. Title compound (165 mg, 29%) wasobtained as colorless oil.

MASS(API-ES); 374 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.0 Hz), 1.67-1.92 (1H,m), 2.00-2.25 (1H, m), 2.40-2.95 (6H, m), 3.95-4.28 (4H, m), 4.34-4.58(1H, m), 6.20 (1H, t, J=2.0 Hz), 6.43 (1H, d, J=16 Hz), 7.23 (1H, d,J=6.4 Hz), 7.40 (1H, d, J=2.0 Hz), 7.55 (1H, dd, J=1.8 Hz, J=16 Hz),7.74 (1H, d, J=2.0 Hz), 7.85 (1H, dd, J=1.6 Hz, J=13 Hz), 8.10 (1H, d,J=1.6 Hz).

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 720

N-{2-[(4-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}phenyl)amino]phenyl}cyclohexanecarboxamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.08-1.42 (5H, m), 1.46-1.78 (11H, m), 2.33(1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.88 (1H, m), 6.26 (1H, d, J=16Hz), 6.80 (2H, d, J=8.5 Hz), 7.02-7.19 (2H, m), 7.28 (1H, dd, J=7.5, 1Hz), 7.33-7.44 (3H, m), 7.59 (1H, dd, J=7.5, 1 Hz), 7.71 (1H, s), 9.23(1H, s), 11.07 (1H, s); MS (ES−) m/z 462.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 721

6-[(2-benzylphenyl)amino]-5-chloronicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 4.04 (2H, s), 7.09 (1H, s), 7.12-7.41 (8H, m),7.85 (1H, d, J=8 Hz), 7.99 (1H, d, J=2 Hz), 8.45 (1H, d, J=2 Hz), 9.80(1H, s); MS (ES+) m/z 323.

The following compound was obtained in a similar manner to that ofPreparation 379.

Preparation 722

ethyl6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate

MASS(API-ES); 378 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.28 (3H, t, J=7.1 Hz), 1.70-1.95 (1H,m), 2.05-2.30 (1H, m), 2.35-2.75 (3H, m), 2.80-2.90 (1H, m), 3.50-3.70(2H, m), 4.23 (2H, q, J=7.1 Hz), 4.30-4.55 (1H, m), 7.15-7.40 (5H, m),7.77 (1H, d, J=11 Hz), 7.89 (1H, d, J=6.4 Hz).

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 723

tert-butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyrimidinyl)[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.47 (3×3H, s), 1.56-1.95 (6H, m), 2.06-2.32(2H, m), 2.56-2.84 (7H, m), 3.08 (1H, dd, J=8, 8 Hz), 3.68 (1H, m), 3.97(1H, m), 4.92-5.10 (2H, m), 6.46 (1H, br), 7.13-7.33 (5H, m), 7.63 (1H,d, J=15.5 Hz), 8.78 (2×1H, s); MS (ES+) m/z 538.

The following compounds were obtained in a similar manner to that ofPreparation 414.

Preparation 724

(2E)-3-(5-{[2-(1-piperidinyl)phenyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.42-1.76 (12H, m), 2.71-2.83 (4H, m), 3.52(1H, m), 3.96 (1H, m), 4.91 (1H, m), 6.74 (1H, d, J=15.5 Hz), 7.03-7.10(2H, m), 7.14 (1H, m), 7.48 (1H, d, J=15.5 Hz), 7.92 (1H, dd, J=6, 3.5Hz), 8.27 (1H, s), 8.32 (1H, s), 8.78 (1H, s), 11.26 (1H, s); MS (ES+)m/z 424.

The following compound was obtained in a similar manner to that ofPreparation 375.

Preparation 725

ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)acrylate

MASS(API-ES); 39.0 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.79 (10H, m), 1.24 (3H, t, J=7.1Hz), 1.80-2.55 (3H, m), 3.15-3.90 (4H, m), 4.16 (2H, q, J=7.1 Hz),4.35-4.75 (1H, m), 6.46 (1H, d, J=16 Hz), 7.38-7.50 (1H, m), 7.56 (1H,d, J=16 Hz), 7.90 (1H, d, J=13 Hz), 8.15 (1H, s).

The following compound was obtained in a similar manner to that ofPreparation 450.

Preparation 726

tert-butyl [(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 1.63 (1H, m), 2.20-2.47 (2H, m),2.56-2.76 (2H, m), 2.79-2.96 (3H, m), 2.97-3.11 (3H, m), 4.20 (1H, m),4.86 (1H, m), 7.10-7.22 (4H, m); MS (ES+) m/z 303.

The following compound was obtained in a similar manner to that ofPreparation 452.

Preparation 727

(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinamine dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.00-2.40 (1H, m), 3.05-4.32 (11H, m),7.17-7.30 (4H, m), 8.59 (2H, br); MS (ES+) m/z 203.

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 728

ethyl(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.75 (1H, m), 2.35-2.50(2H, m), 2.75 (1H, dd, J=10, 6 Hz), 2.79 (1H, dd, J=10, 3 Hz), 2.83-3.19(6H, m), 4.25 (2H, q, J=7 Hz), 4.51 (1H, m), 5.25 (1H, d, J=8 Hz), 6.69(1H, d, J=15.5 Hz), 7.10-7.23 (4H, m), 7.58 (1H, d, J=15.5 Hz), 7.90(1H, d, J=1 Hz), 8.07 (1H, d, J=1 Hz); MS (ES+) m/z 379.

The following compound was obtained in a similar manner to that ofPreparation 397.

Preparation 729

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 461 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.80 (16H, m); 1.82-2.55 (3H, m),3.15-4.10 (6H, m), 4.35-4.70 (1H, m), 4.89 (1H, s), 6.29 (1H, d, J=16Hz), 7.25-7.38 (1H, m), 7.41 (1H, d, J=16 Hz), 7.62 (1H, d, J=12 Hz),8.09 (1H, s).

The following compound was obtained in a similar manner to that ofPreparation 311.

Preparation 730

ethyl(2E)-3-(6-{[(3R)-1-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)acrylate

MASS(API-ES); 406 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.65-1.90 (1H,m), 2.00-2.30 (1H, m), 2.35-2.73 (3H, m), 2.80-2.95 (1H, m), 3.69 (2H,s), 4.15 (2H, q, J=7.1 Hz), 4.30°-4.55 (1H, m), 6.42 (1H, d, J=16 Hz),7.00-7.20 (2H, m), 7.25-7.50 (2H, m), 7.53 (1H, dd, J=1.9 Hz, J=16 Hz),7.84 (1H, dd, J=1.7 Hz, J=13 Hz), 8.09 (1H, d, J=1.7 Hz).

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 731

(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.52-1.94 (7H, m), 2.36-2.50 (2H, m), 2.74(1H, dd, J=10, 6 Hz), 2.78-3.17 (7H, m), 3.65 (1H, m), 3.96 (1H, m),4.51 (1H, m), 5.02 (1H, m), 5.33 (1H, d, J=7 Hz), 6.70 (1H, br),7.12-7.22 (4H, m), 7.63 (1H, d, J=15.5 Hz), 7.88 (1H, s), 8.05 (1H, s);MS (ES+) m/z 450.

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 732

(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d6) δ 1.68 (1H, m), 2.25 (1H, m), 2.44-2.56 (1H,m), 2.71-2.90 (4H, m), 2.94-3.60 (4H, m), 4.35 (1H, m), 6.46 (1H, d,J=15.3 Hz), 7.07-7.22 (4H, m), 7.48 (1H, d, J=15.3 Hz), 7.92 (1H, d,J=6.5 Hz), 8.00 (1H, d, J=1 Hz), 8.20 (1H, d, J=1 Hz); MS (ES+) m/z 351.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 733

tert-butyl[(3R)-1-cyclohexyl-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 1.00-2.15 (18H, m), 2.30-3.20 (5H, m), 3.54(1H, m), 3.96 (1H, m), 4.72 (1H, m), 4.92 (1H, m), 6.59 (1H, d, J=16Hz), 7.36 (1H, d, J=8 Hz), 7.53 (1H, d, J=16 Hz), 8.01 (1H, d, J=8 Hz),8.63 (1H, s), 11.31 (1H, br-s); MS (ES+) m/z 515.

The following compound was obtained in a similar manner to that ofPreparation 397.

Preparation 734

(2E)-3-(6-{[(3R)-1-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 477 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.90 (7H, m), 2.00-2.28 (1H, m),2.30-2.75 (3H, m), 2.80-3.00 (1H, m), 3.40-3.60 (1H, m), 3.69 (2H, s),3.80-4.05 (1H, m), 4.25-4.60 (1H, m), 4.88 (1H, s), 6.25 (1H, d, J=0.15Hz), 7.00-7.25 (3H, m), 7.30-7.75 (3H, m), 8.03 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 336.

Preparation 735

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 441 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.95 (7H, m), 2.05-2.30 (1H, m),2.32-2.70 (3H, m), 2.80-2.90 (1H, m), 3.40-3.65 (3H, m), 3.80-4.10 (1H,m), 4.30-4.60 (1H, m), 4.88 (1H, s), 6.25 (1H, d, J=15 Hz), 7.15 (1H, d,J=6.5 Hz), 7.18-7.45 (6H, m), 7.56 (1H, d, J=12 Hz), 8.02 (1H, s).

Preparation 736

tert-butyl[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyrimidinyl)carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 0.54-0.72 (2H, m), 1.00-1.78 (15H, m), 1.33(3×3H, s), 1.94-2.14 (4H, m), 2.25 (1H, m), 2.37-2.58 (2H, m), 2.68 (1H,m), 3.54 (1H, m), 3.96 (1H, m), 4.76 (1H, m), 4.93 (1H, m), 6.70 (1H, d,J=16 Hz), 7.51 (1H, d, J=16 Hz), 9.01 (2×1H, s), 11.41 (1H, s); MS (ES+)m/z 530.

The following compound was obtained in a similar manner to that ofPreparation 810.

Preparation 737

ethyl(2E)-3-(6-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.4 Hz), 1.26-1.50 (2H, m),1.85-1.90 (2H, m), 1.99-2.11 (2H, m), 2.74-2.80 (2H, m), 3.45 (2H, s),3.77-3.90 (1H, m), 4.14 (2H, q, J=7.4 Hz), 6.29 (1H, d, J=15.9 Hz), 6.48(1H, d, J=7.8 Hz), 7.09-7.18 (3H, m), 7.30-7.37 (2H, m), 7.48 (1H, d,J=15.9 Hz), 7.76 (1H, dd, J=1.9, 8.0 Hz), 8.20 (1H, d, J=1.9 Hz),

Mass (ESI): 384(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 738

ethyl(2E)-3-(6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 0.79-0.91 (2H, m), 1.02-2.15 (17H, m), 1.23 (3H, t,J=7.4 Hz), 2.80 (2H, brs), 3.65-3.85 (1H, m), 4.14 (2H, q, J=7.4 Hz),6.30 (1H, d, J=15.9 Hz), 6.49 (1H, d, J=8.8 Hz), 7.12 (1H, d, J=7.2 Hz),7.49 (1H, d, J=15.9 Hz), 7.76 (1H, dd, J=2.2, 8.8 Hz), 8.20 (1H, d,J=2.2 Hz),

Mass (ESI): 372(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 862.

Preparation 739

(2E)-3-(6-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

Mass (ESI): 356(M+H)+.

Preparation 740

(2E)-3-(6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

Mass (ESI): 344(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 62.

Preparation 741

(2E)-3-(6-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 455 (M+H)+.

Preparation 742

(2E)-3-(6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 443 (M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 375.

Preparation 743

ethyl(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

MASS(API-ES); 472 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.10-1.80 (22H, m), 1.85-2.40 (3H, m),3.00-3.90 (4H, m), 4.21 (2H, q, J=7.1 Hz), 4.61-4.97 (1H, m), 6.78 (1H,d, J=16 Hz), 7.38 (1H, dd, J=3.4 Hz, J=8.6 Hz), 7.69 (1H, d, J=16 Hz),8.22 (1H, d, J=8.6 Hz), 8.73 (1H, d, J=3.4 Hz).

The following compound was obtained in a similar manner to that ofPreparation 397.

Preparation 744

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 443 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.03-2.57 (19H, m), 3.10-4.08 (˜6H, m),4.20-4.60 (1H, m), 4.88 (1H, s), 6.23 (1H, d, J=15 Hz), 6.55 (1H, dd,J=3.2 Hz, J=8.8 Hz), 7.28 (1H, d, J=6.7 Hz), 7.37 (1H, d, J=15 Hz), 7.63(1H, d, J=8.8 Hz), 8.18 (1H, s).

The following compounds were obtained in a similar manner to that ofPreparation 871.

Preparation 745

ethyl 6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloronicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.51 (1H, m), 1.67-2.03(4H, m), 2.33 (1H, m), 3.87 (1H, m), 4.34 (2H, q, J=7 Hz), 4.52 (1H, m),4.67 (1H, d, J=12.7 Hz), 4.69 (1H, d, J=12.7 Hz), 5.27 (1H, d, J=7 Hz),7.22-7.38 (5H, m), 8.01 (1H, d, J=2.2 Hz), 8.71 (1H, d, J=2.2 Hz); MS(ES+) m/z 375.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 746

[6-(2,3-dihydro-1H-inden-2-ylamino)-3-pyridinyl]methanol

¹H-NMR (300 MHz, CDCl₃) δ 2.88 (2H, dd, J=16, 4.5 Hz), 3.39 (2H, dd,J=16, 7 Hz), 4.54 (2H, s), 4.60 (1H, m), 4.82 (1H, br-d, J=6 Hz), 6.43(1H, d, J=9 Hz), 7.114-7.30 (4H, m), 7.49 (1H, dd, J=8.5, 2.5 Hz), 8.06(1H, d, J=2.5 Hz); MS (ES+) m/z 241.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 747

6-(2,3-dihydro-1H-inden-2-ylamino)nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 2.93 (2H, dd, J=16, 4.5 Hz), 3.43 (2H, dd,J=16, 7 Hz), 4.75 (1H, br), 5.42 (1H, br.), 6.45 (1H, d, J=8.8 Hz),7.16-7.30 (4H, m), 7.90 (1H, dd, J=8.8, 2.2 Hz), 8.52 (1H, d, J=2.2 Hz),9.78 (1H, s); MS (ES+) m/z 239.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 748

(2E)-3-[6-(2,3-dihydro-1H-inden-2-ylamino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.45-1.78 (6H, m), 2.83 (2H, dd, J=16, 5.5Hz), 3.29 (1H, dd, J=16, 7 Hz), 3.53 (1H, m), 3.95 (1H, m), 4.64 (1H,m), 4.88 (1H, m), 6.22 (1H, br-d, J=16 Hz), 6.54 (1H, d, J=8.5 Hz),7.11-7.28 (4H, m), 7.31-7.45 (2H, m), 7.61 (1H, br-d, J=8.5 Hz), 8.19(1H, s), 11.16 (1H, br); MS (ES+) m/z 380.

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 749

(2E)-3-{4-[(6-methyl-2-pyridinyl)amino]phenyl}acrylic acid

¹H-NMR (300 MHz, DMSO-d6) δ 2.40 (3H, s), 6.33 (1H, d, J=16 Hz), 6.67(1H, d, J=7.5 Hz), 6.69 (1H, d, J=7.5 Hz), 7.49 (1H, dd, J=7.5, 7.5 Hz),7.51 (1H, d, J=16 Hz), 7.57 (2H, d, J=8.5 Hz), 7.77 (2H, d, J=8.5 Hz),9.29 (1H, s), 12.13 (1H, br); MS (ES+) m/z 255.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 750

(2E)-3-{4-[(6-methyl-2-pyridinyl)amino]phenyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.46-1.76 (6H, m), 2.39 (3H, s), 3.53 (1H,m), 3.96 (1H, m), 4.90 (1H, m), 6.33 (1H, br-d, J=16 Hz), 6.66 (1H, d,J=7 Hz), 6.68 (1H, d, J=7 Hz), 7.37-7.54 (4H, m), 7.77 (2×1H, d, J=8.5Hz), 9.25 (1H, s), 11.12 (1H, s); MS (ES+) m/z 354.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 751

(6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro-3-pyridinyl)methanol

¹H-NMR (300 MHz, CDCl₃) δ 1.49 (1H, m), 1.68-2.02 (4H, m), 2.31 (1H, m),3.87 (1H, m), 4.44 (1H, m), 4.54 (2H, s), 4.66 (1H, d, J=12 Hz), 4.69(1H, d, J=12 Hz), 4.89 (1H, d, J=7.5 Hz), 7.23-7.42 (4H, m), 7.51 (1H,d, J=2 Hz), 8.02 (1H, d, J=2 Hz); MS (ES+) m/z 333.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 752

6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloronicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 1.53 (1H, m), 1.68-2.06 (4H, m), 2.34 (1H, m),3.89 (1H, m), 4.56 (1H, m), 4.67 (2H, s), 5.50 (1H, d, J=7 Hz),7.22-7.38 (5H, m), 7.93 (1H, d, J=2 Hz), 8.47 (1H, d, J=2 Hz), 9.78 (1H,s); MS (ES+) m/z 331.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 753

(2E)-3-(6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.45-1.78 (10H, m), 1.87-2.12 (2H, m), 3.53(1H, m), 3.90-4.02 (2H, m), 4.45 (1H, m), 4.54 (2H, s), 4.89 (1H, m),6.33 (1H, br-d, J=16 Hz), 6.74 (1H, d, J=7.7 Hz), 7.22-7.37 (5H, m),7.37 (1H, d, J=16 Hz), 7.84 (1H, s), 8.24 (1H, s), 11.08 (1H, s); MS(ES+) m/z 472.

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 754

tert-butyl[(3R)-1-cycloheptyl-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 1.13-1.78 (20H, m), 1.89 (1H, m), 2.03 (1H,m), 2.25 (1H, m), 2.62 (1H, m), 2.81 (1H, m), 3.54 (1H, m), 3.95 (1H,m), 4.68 (1H, m), 4.92 (1H, m), 6.58 (1H, d, J=15 Hz), 7.34 (1H, d, J=8Hz), 7.52 (1H, d, J=15 Hz), 8.00 (1H, d, J=8, 2 Hz), 8.62 (1H, d, J=2Hz), 11.32 (1H, br-s); MS (ES+) m/z 529.

The following compound was obtained in a similar manner to that ofPreparation 486.

Preparation 755

tert-butyl, [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]carbamate

¹HNMR (400 MHz, CDCl₃): δ 1.44 (9H, s), 1.54-1.66 (1H, m), 2.20-2.35(2H, m), 2.51-2.64 (2H, m), 2.74-2.84 (1H, m), 3.56, 3.61 (2H, q,Jab=13.2 Hz), 4.18 (1H, br.s), 4.92 (1H, br.s), 7.11 (1H, dt, J=2.7, 8.3Hz), 7.02-7.09 (2H, m), 7.23-7.29 (1H, m),

MASS (ESI): m/z=295.3 (M+1).

The following compound was obtained in a similar manner to that ofPreparation 871.

Preparation 756

ethyl 5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.26 (1H, m), 1.37 (3H, t, J=7 Hz), 1.39 (1H,m), 2.13 (1H, m), 3.10 (1H, m), 4.34 (2H, q, J=7 Hz), 5.70 (1H, br),7.17-7.35 (5H, m), 8.04 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz); MS (ES+)m/z 317.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 757

5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 1.29 (1H, m), 1.44 (1H, m), 2.17 (1H, ddd,J=9, 6, 3 Hz), 3.15 (1H, m), 5.91 (1H, br-s), 7.19-7.36 (5H, m), 7.96(1H, d, J=1.8 Hz), 8.53 (1H, d, J=1.8 Hz), 9.81 (1H, s); MS (ES+) m/z273.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 758

(2E)-3-(5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.24 (1H, m), 1.42 (1H, m), 1.46-1.77 (6H,m), 2.06 (1H, m), 3.03 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.88 (1H,m), 6.33 (1H, d, J=16 Hz), 7.13-7.22 (3H, m), 7.24-7.32 (3H, m), 7.36(1H, d, J=16 Hz), 7.85 (1H, br-s), 8.22 (1H, br-s), 11.09 (1H, br-s);

MS (ES+) m/z 414.

The following compound was obtained in a similar manner to that ofPreparation 871.

Preparation 759

ethyl 5-chloro-6-({3-[(cyclohexylcarbonyl)amino]phenyl}amino)nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.20-1.42 (3H, m), 1.39 (3H, t, J=7 Hz),1.48-1.64 (2H, m), 1.72 (1H, m), 1.80-1.90 (2H, m), 1.92-2.02 (2H, m),2.24 (1H, m), 4.36 (2H, q, J=7 Hz), 7.15-7.36 (4H, m), 7.46 (1H, m),8.09 (1H, s), 8.16 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz); MS (ES+) m/z402.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 760

(2E)-3-{6-[(2-benzylphenyl)amino]-5-chloro-3-pyridinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.46-1.78 (6H, m), 3.53 (1H, m), 3.92 (2H,s), 3.95 (1H, m), 4.89 (1H, m), 6.36 (1H, d, J=16 Hz), 7.07-7.30 (8H,m), 7.37 (1H, d, J=16 Hz), 7.44 (1H; d, J=8 Hz), 7.95 (1H, s), 8.13 (1H,s), 8.23 (1H, s), 11.13 (1H, s); MS (ES+) m/z 464.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 761

N-(3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}phenyl)cyclohexanecarboxamide

¹H-NMR (300 MHz, CDCl₃) δ 1.20-1.40 (3H, m), 1.45-1.75 (3H, m),1.76-2.01 (4H, m), 2.22 (1H, m), 4.59 (2H, s), 7.03 (1H, s), 7.13 (1H,d, J=8 Hz), 7.22-7.32 (2H, m), 7.39 (1H, d, J=8 Hz), 7.65 (1H, d, J=2Hz), 8.04 (1H, s), 8.09 (1H, d, J=2 Hz); MS (ES+) m/z 360.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 762

N-{2-[(3-chloro-5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]phenyl}cyclohexanecarboxamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.12-1.34 (3H, m), 1.36-1.86 (13H, m), 2.41(1H, m), 3.53 (1H, m), 3.96 (1H, m), 4.89 (1H, m), 6.40 (1H, d, J=16Hz), 7.14 (1H, dd, J=7.5, 7.5 Hz), 7.21-7.29 (2H, m), 7.40 (1H, d, J=16Hz), 7.78 (1H, d, J=7.5 Hz), 8.02 (1H, s), 8.22 (1H, s), 8.32 (1H, s),9.92 (1H, s), 11.16 (1H, s); MS (ES+) m/z 499.

The following compound was obtained in a similar manner to that ofPreparation 871.

Preparation 763

ethyl 5-chloro-6-({2-[(cyclohexylcarbonyl)amino]phenyl}amino)nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.20-1.40 (3H, m), 1.37 (3H, t, J=7 Hz),1.43-1.59 (2H, m), 1.69 (1H, m), 1.75-1.99 (4H, m), 2.27 (1H, m), 4.35(2H, q, J=7 Hz), 7.19 (1H, ddd, J=7.7, 7.7, 1.5 Hz), 7.24-7.37 (2H, m),7.58 (1H, s), 7.70 (1H, dd, J=7.7, 1.5 Hz), 7.95 (1H, s), 8.15 (1H, d,J=1.7 Hz), 8.67 (1H, d, J=1.7 Hz); MS (ES+) m/z 402.

The following compounds were obtained in a similar manner to that ofPreparation 382.

Preparation 764

N-{2-[(3-chloro-5-formyl-2-pyridinyl)amino]phenyl)cyclohexanecarboxamide

¹H-NMR (300 MHz, CDCl₃) δ 1.18-1.38 (3H, m), 1.42-1.64 (2H, m), 1.70(1H, m), 1.76-1.88 (2H, m), 1.90-2.00 (2H, m), 2.30 (1H, m), 7.17-7.36(5H, m), 7.50 (1H, s), 7.77 (1H, d, J=7.5 Hz), 8.05 (1H, d, J=1.5 Hz),8.34 (1H, s), 8.44 (1H, d, J=1.5 Hz), 9.81 (1H, s); MS (ES+) m/z 358.

Preparation 765

N-{3-[(3-chloro-5-formyl-2-pyridinyl)amino]phenyl)cyclohexanecarboxamide

¹H-NMR (300 MHz, CDCl₃) δ 1.22-1.41 (3H, m), 1.48-1.64 (2H, m), 1.72(1H, m), 1.79-1.91 (2H, m), 1.92-2.02 (2H, m), 2.25 (1H, m), 7.17 (1H,d, J=8 Hz), 7.23 (1H, s), 7.33 (1H, dd, J=8, 8 Hz), 7.44-7.54 (2H, m),8.07 (1H, d, J=2 Hz), 8.14 (1H, s), 8.56 (1H, d, J=2 Hz), 9.85 (1H, s);MS (ES+) m/z 358.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 766

N-(3-[(3-chloro-5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]phenyl)cyclohexanecarboxamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.13-1.85 (16H, m), 2.33 (1H, m), 3.53 (1H,m), 3.96 (1H, m), 4.90 (1H, m), 6.43 (1H, d, J=16 Hz), 7.16-7.34 (4H,m), 7.43 (1H, d, J=16 Hz), 7.95 (1H, s), 8.03 (1H, s), 8.29 (1H, s),8.66 (1H, s), 9.79 (1H, s), 11.19 (1H, s); MS (ES+) m/z 499.

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 767

(2E)-3-(5-{[2-(1-piperidinyl)phenyl]amino}-2-pyrazinyl)acrylic acid

¹H-NMR (300 MHz, DMSO-d6) δ 1.50 (2H, m), 1.56-1.68 (4H, m), 2.76-2.88(4H, m), 6.58 (1H, d, J=15.5 Hz), 7.04-7.14 (2H, m), 7.17 (1H, m), 7.56(1H, d, J=15.5 Hz), 7.90 (1H, m), 8.33-8.38 (2H, m), 8.92 (1H, br-s);

MS (ES+) m/z 325.

The following compound was obtained in a similar manner to that ofPreparation 366.

Preparation 768

ethyl (2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylatedihydrochloride

MASS(API-ES); 280 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.90-2.35 (2H,m), 3.05-3.60 (4H, m), 4.17 (2H, q, J=7.1 Hz), 4.55-4.75 (1H, m), 6.50(1H, d, J=16 Hz), 7.58 (1H, dd, J=1.8 Hz, J=16 Hz), 7.65 (1H, br), 7.97(1H, dd, J=1.6 Hz, J=13 Hz), 8.17 (1H, d, J=1.6 Hz), 9.47 (2H, br).

The following compound was obtained in a similar manner to that ofPreparation 452.

Preparation 769

(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinamine trihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.21 (1H, m), 2.44 (1H, m), 3.55 (1H, m),3.66 (1H, m), 3.76-3.9.4 (2H, m), 4.04 (1H, m), 4.91 (2H, s), 7.69 (1H,m), 7.73 (1H, d, J=8.5 Hz), 7.86 (1H, ddd, J=7, 7, 1.5 Hz), 8.03-8.13(2H, m), 8.52 (1H, d, J=8.5 Hz), 8.77 (2H, br-s); MS (ES+) m/z 228.

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 770

ethyl(2E)-3-(5-{[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.76 (1H, m), 2.42 (1H,m), 2.54 (1H, m), 2.75-2.88 (2H, m), 3.03 (1H, m), 3.98 (1H, d, J=13.5Hz), 4.02 (1H, d, J=13.5 Hz), 4.25 (2H, q, J=7 Hz), 4.51 (1H, m), 5.39(1H, d, J=8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.49-7.62 (3H, m), 7.71 (1H,ddd, J=7, 7, 1.5 Hz), 7.81 (1H, dd, J=8, 1.5 Hz), 7.89 (1H, d, J=1 Hz),8.04 (1H, d, J=1 Hz), 8.08 (1H, d, J=8 Hz), 8.15 (1H, d, J=8 Hz);

MS (ES+) m/z 404.

The following compound was obtained in a similar manner to that ofPreparation 390.

Preparation 771

(2E)-3-(5-fluoro-6-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-3-pyridinyl}acrylicacid

MASS(API-ES); 356 (M+H)+

The following compound was obtained in a similar manner to that ofPreparation 452.

Preparation 772

(3R)-1-(2-methylbenzyl)-3-pyrrolidinamine dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.00-2.65 (2H, m), 2.46 (3H, s), 3.16-4.16(5H, m), 4.37-4.62 (2H, m), 7.22-7.38 (3H, m), 7.60 (1H, m), 8.44-8.75(2H, m); MS (ES+) m/z 191.

The following compounds were obtained in a similar manner to that ofPreparation 450.

Preparation 773

tert-butyl [(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 2.25 (1H, m), 2.51 (1H, m), 2.77(1H, m), 3.02 (1H, m), 3.14-3.40 (4H, m), 3.64 (1H, m), 3.90 (1H, m),4.63 (1H, m), 6.45 (1H, d, J=8.5 Hz), 7.20-7.38 (5H, m); MS (ES+) m/z291.

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 774

ethyl(2E)-3-(5-{[(3R)-1-(2-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.69 (1H, m), 2.29-2.45(2H, m), 2.38 (3H, s), 2.66 (1H, dd, J=10, 3 Hz), 2.70 (1H, dd, J=10, 6Hz), 2.91 (1H, m), 3.62 (2H, s), 4.25 (2H, q, J=7 Hz), 4.45 (1H, m),5.19 (1H, d, J=8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.11-7.20 (3H, m), 7.26(1H, m), 7.56 (1H, d, J=15.5 Hz), 7.87 (1H, d, J=1 Hz), 8.05 (1H, d, J=1Hz); MS (ES+) m/z 367.

The following compound was obtained in a similar manner to that ofPreparation 397.

Preparation 775

(2E)-3-(5-fluoro-6-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 455 (M+H)+.

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.95 (7H, m), 2.00-2.30 (1H, m),2.45-2.80 (7H, m), 2.85-3.00 (1H, m), 3.40-3.65 (1H, m), 3.80-4.10 (1H,m), 4.35-4.60 (1H, m), 4.89 (1H, s), 6.27 (1H, d, J=16 Hz), 7.05-7.35(6H, m), 7.39 (1H, d, J=16 Hz), 7.58 (1H, d, J=12 Hz), 8.05 (1H, s).

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 776

ethyl(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.78-0.96 (2H, m), 1.10-1.29 (4H, m), 1.33(3H, t, J=7 Hz), 1.43 (1H, m), 1.58-1.84 (5H, m), 2.18-2.38 (4H, m),2.61 (2H, d, J=5 Hz), 2.83 (1H, m), 4.25 (2H, q, J=7 Hz), 4.53 (1H, m),5.75 (1H, d, J=8 Hz), 6.30 (1H, d, J=16 Hz), 7.48 (1H, d, J=16 Hz), 8.44(2×1H, s); MS (ES+) m/z 359.

The following compound was obtained in a similar manner to that ofPreparation 480.

Preparation 777

tert-butyl [(3R)-1-(1-phenylethyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (1.5H, d, J=6.6 Hz), 1.37 (1.5H, d, J=6.6Hz), 1.42 (4.5H, s), 1.44 (4.5H, s), 1.47-1.68 (1H, m), 2.10-2.36 (2.5H,m), 2.49-2.68 (2H, m), 2.88 (0.5H, m), 3.19 (1H, q, J=6.6 Hz), 4.12 (1H,m), 4.82 (1H, m), 7.19-7.36 (5H, m); MS (ES+) m/z 291.

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 778

(2E)-3-(5-{[(3R)-1-(1-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.29 (1.5H, d, J=6.5 Hz), 1.30 (1.5H, d,J=6.5 Hz), 1.46-1.76 (7H, m), 2.11-2.34 (2H, m), 2.37-2.56 (1H, m),2.65-2.83 (2H, m), 3.20-3.42 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.27(1H, m), 4.89 (2H, m), 6.60 (1H, d, J=15 Hz), 7.19-7.37 (5H, m), 7.36(1H, d, J=15 Hz), 7.73 (0.5H, d, J=6 Hz), 7.76 (0.5H, d, J=6 Hz), 7.97(1H, s), 8.08 (0.5H, s), 8.09 (0.5H, s), 11.18 (1H, br-s); MS (ES+) m/z438.

The following compounds were obtained in a similar manner to that ofPreparation 452.

Preparation 779

(3R)-1-(1-phenylethyl)-3-pyrrolidinamine

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (1.5H, d, J=6.6 Hz), 1.38 (1.5H, d, J=6.6Hz), 1.39-1.70 (3H, m), 2.08-2.23 (1.5H, m), 2.32 (1H, m), 2.54 (1H, dd,J=7, 7 Hz), 2.62 (0.5H, dd, J=9.5, 6.5 Hz), 2.67-2.82 (1H, m), 3.20 (1H,q, J=6.6 Hz), 3.46 (1H, m), 7.18-7.36 (5H, m); MS (ES+) m/z 191.

Preparation 780

(3R)-1-(2-phenylethyl)-3-pyrrolidinamine

¹H-NMR (300 MHz, CDCl₃) δ 1.42-1.66 (3H, m), 2.21 (1H, dddd, J=13, 8.5,8.5, 5.5 Hz), 2.37 (1H, dd, J=9.5, 4.5 Hz), 2.53 (1H, ddd, J=8.5, 8.5,6.5 Hz), 2.60-2.86 (4H, m), 3.53 (1H, m), 7.15-7.33 (5H, m); MS (ES+)m/z 191.

Preparation 781

(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinamine

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (2H, br), 1.52 (1H, m), 2.24 (1H, dddd,J=13, 8.5, 8.5, 5 Hz), 2.36 (1H, dd, J=9.5, 5 Hz), 2.59 (1H, ddd, J=8.5,8.5, 6 Hz), 2.77 (1H, ddd, J=8.5, 8.5, 6 Hz), 2.82-2.97 (3H, m),2.98-3.14 (3H, m), 3.57 (1H, m), 7.08-7.22 (4H, m); MS (ES+) m/z 203.

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 782

(2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d6) δ 1.00-2.38 (12H, m), 1.39 (3H, s), 1.42 (6H,s), 3.00-4.00 (5H, m), 4.97 (1H, m), 6.68 (0.7H, d, J=16 Hz), 6.70(0.3H, d, J=16 Hz), 7.43 (1H, d, J=8.5 Hz), 7.63 (0.7H, d, J=16 Hz),7.64 (0.3H, d, J=16 Hz), 8.23 (1H, m), 8.73 (1H, m), 11.48 (1H, br); MS(ES+) m/z 416.

The following compound was obtained in a similar manner to that ofPreparation 452.

Preparation 783

(3R)-3-amino-1-(cyclohexylmethyl)-2-pyrrolidinone

¹H-NMR (300 MHz, CDCl₃) δ 0.86-1.06 (2H, m), 1.10-1.30 (3H, m),1.52-1.80 (9H, m), 2.42 (1H, m), 3.08 (1H, dd, J=14, 7 Hz), 3.15 (1H,dd, J=14, 7 Hz), 3.23-3.35 (2H, m), 3.53 (1H, dd, J=10, 8.5 Hz); MS(ES+) m/z 197.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 784

(2E)-3-(5-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 0.73-0.93 (2H, m), 1.06-1.28 (3H, m),1.30-1.83 (13H, m), 2.10-2.30 (3H, m), 2.31-2.44 (2H, m), 2.61 (1H, m),2.72 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.29 (1H, m), 4.89 (1H, m),6.60 (1H, d, J=15.2 Hz), 7.38 (1H, d, J=15.2 Hz), 7.73 (1H, d, J=6.6Hz), 7.98 (1H, s), 8.11 (1H, s), 11.18 (1H, s); MS (ES+) m/z 430.

The following compound was obtained in a similar manner to that ofPreparation 480.

Preparation 785

tert-butyl [(3R)-1-(2-methylbenzyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 1.67 (1H, m), 2.16-2.33 (2H, m),2.52 (1H, m), 2.59 (1H, dd, J=9.5, 6 Hz), 2.79 (1H, m), 3.56 (2H, s),4.16 (1H, m), 4.80 (1H, m), 7.10-7.20 (3H, m), 7.25 (1H, m); MS (ES+)m/z 291.

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 786

(2E)-3-(5-{([(3R)-1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 0.80-0.96 (2H, m), 1.10-1.30 (3H, m),1.45-1.76 (12H, m), 1.84 (1H, m), 2.44 (1H, m), 2.97-3.12 (2H, m),3.27-3.39 (2H, m), 3.52 (1H, m), 3.95 (1H, m), 4.64 (1H, m), 4.90 (1H,m), 6.64 (1H, d, J=15.5 Hz), 7.41 (1H, d, J=15.5 Hz), 7.88 (1H, d, J=7.5Hz), 8.06 (1H, s), 8.10 (1H, s), 11.21 (1H, s); MS (ES+) m/z 444.

The following compound was obtained in a similar manner to that ofPreparation 390.

Preparation 787

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl}acrylicacid

MASS(API-ES); 362 (M+H)+.

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.79 (10H, m), 1.80-2.55 (3H, m),3.15-3.90 (4H, m), 4.40-4.70 (1H, m), 6.36 (1H, d, J=16 Hz), 7.35-7.45(1H, m), 7.51 (1H, d, J=16 Hz), 7.86 (1H, dd, J=1.8 Hz, J=12 Hz), 8.12(1H, d, J=1.8 Hz).

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 788

(2E)-3-(5-{[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.46-1.77 (7H, m), 2.26 (1H, m), 2.46-2.60(2H, m), 2.77 (1H, m), 2.89 (1H, dd, J=9.5, 7 Hz), 3.52 (1H, m), 3.90(2H, s), 3.95 (1H, m), 4.35 (1H; m), 4.89 (1H, m), 6.59 (1H, d, J=15Hz), 7.37 (1H, d, J=15 Hz), 7.57 (1H, m), 7.65 (1H, d, J=8.5 Hz), 7.73(1H, m), 7.81 (1H, d, J=7 Hz), 7.93-8.02 (3H, m), 8.09 (1H, s), 8.33(1H, d, J=8.5 Hz), 11.18 (1H, s); MS (ES+) m/z 475.

The following compound was obtained in a similar manner to that ofPreparation 859.

Preparation 789

ethyl(2E)-3-(2-{(tert-butoxycarbonyl)[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 1.47 (3×3H, s),2.07-2.33 (2H, m), 2.56-2.83 (7H, m), 3.08 (1H, dd, J=8, 8 Hz), 4.29(2H, q, J=7 Hz), 5.00 (1H, m), 6.54 (1H, d, J=16 Hz), 7.14-7.33 (5H, m),7.59 (1H, d, J=16 Hz), 8.79 (2×1H, s); MS (ES+) m/z 467.

The following compound was obtained in a similar manner to that ofPreparation 436.

Preparation 790

methyl5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-2-pyrazinecarboxylate

MASS(API-ES); 413 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.39 (10H, s), 1.95-2.30 (2H, m),2.40-2.85 (3H, m), 3.45, 3.53 (2H, ABq, J=13 Hz), 3.93 (3H, s),4.70-4.95 (1H, m), 7.05-7.30 (5H, m), 8.79 (1H, d, J=1.3 Hz), 9.00 (1H,d, J=1.3 Hz).

The following compound was obtained in a similar manner to that ofPreparation 379.

Preparation 791

methyl 5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinecarboxylate

MASS(API-ES); 313 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.55-1.80 (1H, m), 2.10-2.55 (3H, m),2.60-2.85 (2H, m), 3.59 (2H, s), 3.78 (3H, s), 4.25-4.45 (1H, m),7.20-7.35 (5H, m), 7.96 (1H, d, J=1.0 Hz), 8.16 (1H, d, J=6.7 Hz), 8.56(1H, d, J=1.0 Hz).

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 792

ethyl(2E)-3-(5-{[(3R)-1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.88-1.06 (2H, m), 1.12-1.36 (3H, m), 1.33(3H, t, J=7 Hz), 1.54-1.80 (5H, m), 1.87 (1H, m), 2.85 (1H, m), 3.16(1H, dd, J=14, 7 Hz), 3.22 (1H, dd, J=14, 7 Hz), 3.30-3.50 (2H, m), 4.25(2H, q, J=7 Hz), 4.47 (1H, m), 5.75 (1H, d, J=4 Hz), 6.72 (1H, d, J=15.5Hz), 7.57 (1H, d, J=15.5 Hz), 8.01 (1H, d, J=1 Hz), 8.05 (1H, d, J=1Hz); MS (ES+) m/z 373.

The following compound was obtained in a similar manner to that ofPreparation 480.

Preparation 793

tert-butyl [(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.64 (1H, m), 2.29 (1H, m), 2.48(1H, m), 2.62 (1H, m), 2.78 (1H, dd, J=9.5, 6.5 Hz), 2.89 (1H, m), 3.95(2H, s), 4.21 (1H, m), 4.96 (1H, br-d, J=8 Hz), 7.52 (1H, m), 7.56 (1H,d, J=8.5 Hz), 7.70 (1H, m), 7.81 (1H, dd, J=8, 1.5 Hz), 8.08 (1H, d, J=8Hz), 8.13 (1H, d, J=8.5 Hz); MS (ES+) m/z 328.

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 794

(2E)-3-(5-{[(3R)-1-(2-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.42-1.78 (7H, m), 2.24 (1H, m), 2.32 (3H,s), 2.36-2.53 (2H, m), 2.66 (1H, m), 2.79 (1H, m), 3.52 (1H, m), 3.55(2H, s), 3.95 (1H, m), 4.30 (1H, m), 4.89 (1H, m), 6.60 (1H, d, J=15Hz), 7.09-7.18 (3H, m), 7.26 (1H, m), 7.37 (1H, d, J=15 Hz), 7.76 (1H,d, J=6.5 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.18 (1H, s); MS (ES+) m/z438.

The following compound was obtained in a similar manner to that ofPreparation 450.

Preparation 795

tert-butyl [(3R)-1-(4-ethoxybenzyl)-3-pyrrolidinyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7 Hz), 1.43 (3×3H, s), 1.61(1H, m), 2.16-2.39 (2H, m), 2.48-2.67 (2H, m), 2.81 (1H, m), 3.56 (2H,s), 4.02 (2H, q, J=7 Hz), 4.18 (1H, m), 4.96 (1H, m), 6.84 (2×1H, d,J=8.5 Hz), 7.21 (2×1H, d, J=8.5 Hz); MS (ES+) m/z 321.

The following compound was obtained in a similar manner to that ofPreparation 452.

Preparation 796

(3R}-1-(4-ethoxybenzyl)-3-pyrrolidinamine

¹H-NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7 Hz), 1.44-1.58 (3H, m), 2.19(1H, dddd, J=13, 8.5, 8, 6 Hz), 2.27 (1H, dd, J=9, 4.5 Hz), 2.46 (1H,ddd, J=8.5, 8.5, 6 Hz), 2.68 (1H, ddd, J=8.5, 8.5, 6 Hz), 2.71 (1H, dd,J=9, 5.5 Hz), 3.49 (1H, m), 3.51 (1H, d, J=12.5 Hz), 3.56 (1H, d, J=12.5Hz), 4.02 (2H, q, J=7 Hz), 6.84 (2×1H, d, J=8.7 Hz), 7.21 (2×1H, d,J=8.7 Hz); MS (ES+) m/z 221.

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 797

ethyl(2E)-3-(5-{[(3R)-1-(4-ethoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz),1.68 (1H, m), 2.28-2.44 (2H, m), 2.60-2.70 (2H, m), 2.88 (1H, m), 3.55(1H, d, J=13 Hz), 3.59 (1H, d, J=13 Hz), 4.02 (2H, q, J=7 Hz), 4.25 (2H,q, J=7 Hz), 4.45 (1H, m), 5.24 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=15.5Hz), 6.85 (2×1H, d, J=8.5 Hz), 7.21 (2×1H, d, J=8.5 Hz), 7.56 (1H, d,J=15.5 Hz), 7.86 (1H, d, J=1 Hz), 8.04 (1H, d, J=1 Hz); MS (ES+) m/z397.

The following compound was obtained in a similar manner to that ofPreparation 336.

Preparation 798

(2E)-3-(5-{[(3R)-1-(4-ethoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.31 (3H, t, J=7 Hz), 1.44-1.76 (7H, m),2.21 (1H, m), 2.31-2.45 (2H, m), 2.63 (1H, m), 2.73 (1H, dd, J=9.5, 7Hz), 3.33 (1H, m), 3.50 (2H, s), 3.53 (1H, m), 3.96 (1H, m), 3.98 (2H,q, J=7 Hz), 4.29 (1H, m), 4.89 (1H, m), 6.60 (1H, d, J=16 Hz), 6.85(2×1H, d, J=8.5 Hz), 7.19 (2×1H, d, J=8.5 Hz), 7.37 (1H, d, J=15.5 Hz),7.76 (1H, d, J=6.5 Hz), 7.96 (1H, s), 8.09 (1H, s), 11.09 (1H, s);

MS (ES+) m/z 468.

The following compound was obtained in a similar manner to that ofPreparation 380.

Preparation 799

tert-butyl(3R)-3-{[3-fluoro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate

MASS(API-ES); 312 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.30-1.50 (9H, m), 1.65-2.25 (2H, m),3.05-3.70 (4H, m), 4.34 (2H, d, J=5.6 Hz), 4.30-4.50 (1H, m), 5.07 (1H,t, J=5.6 Hz), 6.68 (1H, d, J=6.1 Hz), 7.30 (1H, dd, J=1.7 Hz, J=12 Hz),7.79 (1H, d, J=1.7 Hz).

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 800

(2E)-3-{6-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-2-pyrazinyl)acrylicacid

¹H-NMR (300 MHz, CDCl₃) δ 1.48 (9H, s), 2.38-2.57 (2H, m), 3.22-3.47(3H, m), 3.97 (1H, m), 4.10 (1H, d, J=12.5 Hz), 4.42 (1H, d, J=12.5 Hz),5.20 (1H, m), 7.26 (1H, d, J=15.5 Hz), 7.36-7.45 (3H, m), 7.49 (1H, d,J=15.5 Hz), 7.49-7.58 (2H, m), 8.28 (1H, s), 8.60 (1H, s); MS (ES+) m/z425.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 801

tert-butyl[(3R)-1-benzyl-3-pyrrolidinyl](6-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyrazinyl)carbamate

¹H-NMR (300 MHz, DMSO-d6) δ 1.35 (9H, s), 1.44-1.76 (6H, m), 1.92-2.44(3H, m), 2.62-2.75 (2H, m), 3.15-3.59 (4H, m), 3.96 (1H, m), 4.78 (1H,m), 4.95 (1H, m), 6.97 (1H, d, J=15.5 Hz), 7.04 (2×1H, d, J=7 Hz),7.14-7.28 (3H, m), 7.61 (1H, d, J=15.5 Hz), 8.58 (1H, s), 8.71 (1H, s),11.51 (1H, br-s); MS (ES+) m/z 524.

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 802

ethyl(2E)-3-(2-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.72 (1H, m), 2.30-2.48(2H, m), 2.64-2.86 (6H, m), 2.95 (1H, m), 4.25 (2H, q, J=7 Hz), 4.56(1H, m), 5.73 (1H, d, J=7 Hz), 6.30 (1H, d, J=16 Hz), 7.14-7.34 (5H, m),7.49 (1H, d, J=16 Hz), 8.45 (2×1H, s); MS (ES+) m/z 367.

The following compounds were obtained in a similar manner to that ofPreparation 336.

Preparation 803

(2Z)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 442 (M+H)+,

¹H-NMR (200 MHz), (CDCl₃, δ): 1.50-2.00 (7H, m), 2.30-2.60 (2H, m),2.70-3.10 (3H, m), 3.30-3.70 (1H, m), 3.72 (2H, s), 3.95-4.20 (1H, m),4.40-4.60 (1H, m), 5.00-5.10 (1H, m), 6.89 (1H, d, J=39 Hz), 7.20-7.45(5H, m), 7.89 (1H, d, J=1.3 Hz), 8.35 (1H, d, J=1.3 Hz).

(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 442 (M+H)+,

¹H-NMR (200 MHz), (CDCl₃, δ): 1.50-2.00 (7H, m), 2.10-2.55 (2H, m),2.65-2.85 (2H, m), 2.90-3.10 (1H, m), 3.60-3.80 (1H, m), 3.71 (2H, s),3.95-4.15 (1H, m), 4.40-4.60 (1H, m), 5.07 (1H, s), 5.69 (1H, d, J=7.7Hz), 6.60 (1H, d, J=25 Hz), 7.20-7.43 (5H, m), 7.77 (1H, d, J=1.0 Hz),8.04 (1H, d, J=1.0 Hz).

The following compound was obtained in a similar manner to that ofPreparation 311.

Preparation 804

ethyl(2E)-3-(5-fluoro-6-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate

MASS(API-ES); 384 (M+H)+,

¹H-NMR (400 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.0 Hz), 1.70-1.90 (1H,m), 2.00-2.25 (1H, m), 2.30-2.83 (7H, m), 2.85-2.95 (1H, m), 4.16 (2H,q, J=7.0 Hz), 4.35-4.55 (1H, m), 6.43 (1H, d, J=16 Hz), 7.00-7.30 (6H,m), 7.55 (1H, dd, J=2.0 Hz, J=16 Hz), 7.85 (1H, dd, J=1.8 Hz, J=13 Hz),8.11 (1H, d, J=1.8 Hz).

The following compound was obtained in a similar manner to that ofPreparation 390.

Preparation 805

(2E)-3-[5-fluoro-6-({(3R)-1-[2-(1H-pyrazol-1-yl)ethyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylicacid

MASS(API-ES); 346 (M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 397.

Preparation 806

(2E)-3-[5-fluoro-6-({(3R)-1-[2-(1H-pyrazol-1-yl)ethyl]-3-pyrrolidinyl}amino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 445 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.88 (7H, m), 2.00-2.25 (1H, m),2.38-2.95 (6H, m), 3.43-3.62 (1H, m), 3.83-4.05 (1H, m), 4.20 (2H, t,J=6.6 Hz), 4.32-4.55 (1H, m), 4.88 (1H, s), 6.20 (1H, t, J=1.7 Hz), 6.26(1H, d, J=16 Hz), 7.10 (1H, d, J=6.2 Hz), 7.39 (1H, d, J=16 Hz), 7.40(1H, d, J=1.7 Hz), 7.57 (1H, d, J=12 Hz), 7.74 (1H, d, J=1.7 Hz), 8.04(1H, s).

Preparation 807

To a stirred solution of 5-bromo-2-chloropyrimidine (500 mg) in DMF (5mL) was added ethyl acrylate (1.41 mL), palladium(II) acetate (29 mg),tris(2-methylphenyl)phosphine (118 mg), and N,N-diisopropylethylamine(1.35 mL). The mixture was stirred at 100° C. for 4 hours. The resultingmixture was allowed to cool to ambient temperature, poured into brine,and extracted with ethyl acetate. The organic phase was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (90:10 v/v) to give ethyl(2E)-3-(2-chloro-5-pyrimidinyl)acrylate (494 mg) as a yellow powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz),6.59 (1H, d, J=16 Hz), 7.58 (1H, d, J=16 Hz), 8.76 (2×1H, s); MS ( ) m/znot detected.

The following compound was obtained in a similar manner to that ofPreparation 439.

Preparation 808

ethyl(2E)-3-(5-{[(3R)-1-(1-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.32 (1.5H, t, J=7 Hz), 1.33 (1.5H, t, J=7Hz), 1.39 (1.5H, d, J=6.6 Hz), 1.41 (1.5H, d, J=6.6 Hz), 1.56-1.80 (1H,m), 2.26-2.40 (2H, m), 2.46 (0.5H, dd, J=10, 3 Hz), 2.56-2.72 (1.5H, m),2.79 (0.5H, dd, J=10, 3 Hz), 3.04 (1H, m), 3.26 (1H, q, J=6.6 Hz), 4.24(1H, q, J=7 Hz), 4.25 (1H, q, J=7 Hz), 4.42 (1H, m), 5.18 (0.5H, d,J=7.5 Hz), 5.25 (0.5H, d, J=7.5 Hz), 6.67 (0.5H, d, J=15.5 Hz), 6.69(0.5H, d, J=15.5 Hz), 7.20-7.37 (5H, m), 7.55 (0.5H, d, J=15.5 Hz), 7.57(0.5H, d, J=15.5 Hz), 7.86 (0.5H, d, J=1 Hz), 7.90 (0.5H, d, J=1 Hz),8.03 (0.5H, d, J=1 Hz), 8.06 (0.5H, d, J=1 Hz); MS (ES+) m/z 367.

The following compound was obtained in a similar manner to that ofPreparation 390.

Preparation 809

(2E)-3-(6-{[(3R)-1-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl}acrylicacid

MASS(API-ES); 378 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.60-2.25 (2H, m), 2.30-2.70 (3H, m),2.80-3.00 (1H, m), 3.69 (2H, s), 4.30-4.55 (1H, m), 6.31 (1H, d, J=16Hz), 7.00-7.44 (4H, m), 7.45 (1H, d, J=16 Hz), 7.80 (1H, d, J=13 Hz),8.05 (1H, s).

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 810

ethyl(2E)-3-(5-chloro-6-{[1-(2-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 1.24(3H, t, J=7.1 Hz), 1.55-1.89(4H, m),2.05-2.17(2H, m), 2.81-2.87(2H, m), 3.59(2H, s), 3.90-4.10(1H, m),4.16(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.65(1H, d, J=8.0 Hz),7.23-7.29(1H, m), 7.43(1H, d, J=7.8 Hz), 7.50(1H, d, J=16.0 Hz),7.73-7.81(1H, m), 8.10(1H, d, J=1.9 Hz), 8.27(1H, d, J=1.9 Hz), 8.49(1H,d, J=4.1 Hz),

Mass (APCI): 401(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 850.

Preparation 811

ethyl(2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 1.24(3H, t, J=7.1 Hz), 1.60-1.84(4H, m),2.03-2.13(2H, m), 2.78-2.83(2H, m), 3.51(2H, s), 3.91-4.10(1H, m),4.16(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.64(1H, d, J=7.9 Hz),7.32(2H, d, J=5.8 Hz), 7.50(1H, d, J=15.9 Hz), 8.10(1H, d, J=1.9 Hz),8.27(1H, d, J=1.9 Hz), 7.51(1H, d, J=5.8 Hz),

Mass (APCI): 401(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 62.

Preparation 812

(2E)-3-(5-chloro-6-{[1-(2-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 1.50-1.84(10H, m), 2.08-2.18(2H, m), 2.81-2.87(2H,m), 8.49-8.54(1H, m), 8.60(2H, s), 3.93-4.08(2H, m), 4.88(1H, brs),6.30(1H, d, J=15.9 Hz), 6.53(1H, d, J=7.9 Hz), 7.23-7.29(1H, m),7.38(1H, d, J=15.9 Hz), 7.43(1H, d, J=7.9 Hz), 7.23-7.84(2H, m),8.20(1H, s), 8.49(1H, d, J=4.2 Hz), 11.07(1H, brs),

Mass (APCI): 472(M+H)+.

Preparation 813

(2E)-3-(5-chloro-6-{[1-(2-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 1.45-1.90(10H, m), 2.10-2.20(2H, m), 2.82-2.89(2H,m), 3.49-3.60(1H, m), 3.57(2H, s), 3.80-4.10(2H, m), 4.89(1H, brs),6.30(1H, d, J=15.9 Hz), 6.53(1H, d, J=7.9 Hz), 7.27-7.50(5H, m),7.84(1H, s), 8.21(1H, s), 11.07(1H, brs),

Mass (APCI): 505(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 366.

Preparation 814

ethyl (2E)-3-{4-[(3R)-3-pyrrolidinylamino]phenyl}acrylate hydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.24 (3H, t, J=7 Hz), 1.89 (1H, m), 2.21(1H, m), 3.04 (1H, m), 3.16-3.50 (4H, m), 4.14 (2H, q, J=7 Hz), 6.30(1H, d, J=16 Hz), 6.62 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 7.50(1H, d, J=8.5 Hz), 9.20-9.38 (2H, br).

The following compound was obtained in a similar manner to that ofPreparation 678.

Preparation 815

ethyl(2E)-3-(4-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}phenyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.80-0.97 (2H, m), 1.10-1.31 (3H, m), 1.32(3H, t, J=7 Hz), 1.44 (1H, m), 1.58-1.84 (4H, m), 2.18-2.42 (4H, m),2.56 (1H, dd, J=9.5, 3 Hz), 2.68 (1H, dd, J=9.5, 6.5 Hz), 2.78 (1H, m),4.01 (1H, m), 4.24 (2H, q, J=7 Hz), 4.30 (1H, m), 6.21 (1H, d, J=15.8Hz), 6.56 (2×1H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.59 (1H, d,J=15.8 Hz); MS (ES+) m/z 357.

The following compound was obtained in a similar manner to that ofPreparation 434.

Preparation 816

ethyl(2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}phenyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.10-2.12 (11H, m), 1.33 (3H, t, J=7 Hz),2.18-2.42 (2H, m), 3.42 (1H, m), 3.55-3.70 (2H, m), 3.84° (1H, m), 4.06(1H, m), 4.18 (1H, m), 4.24 (1H, q, J=7 Hz), 4.25 (1H, q, J=7 Hz), 6.23(0.5H, d, J=15.8 Hz), 6.24 (0.5H, d, J=15.5 Hz), 6.58 (1H, d, J=7.7 Hz),6.59 (1H, d, J=7.7 Hz), 7.38 (1H, d, J=7.7 Hz), 7.40 (1H, d, J=7.7 Hz),7.59 (0.5H, d, J=15.8 Hz), 7.60 (0.5H, d, J=15.8 Hz); MS (ES+) m/z 371.

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 817

ethyl(2E)-3-(5-chloro-6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 0.78-0.90 (2H, m), 1.14-1.36 (3H, m), 1.23 (3H, t,J=7.4 Hz), 1.41-2.08 (13H, m), 2.77-2.83 (2H, m), 3.92-4.01 (1H, m),4.15 (2H, q, J=7.4 Hz), 6.48 (1H, d, J=15.9 Hz), 6.59 (1H, d, J=7.8 Hz),7.50 (1H, d, J=15.9 Hz), 8.09 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 Hz),

Mass (ESI): 406(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 818

(2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}phenyl)acrylicacid

¹H-NMR (300 MHz, CDCl₃) δ 1.16-2.43 (13H, m), 3.36-3.70 (3H, m), 3.83(1H, m), 4.04-4.24 (1H, m), 6.24 (0.5H, d, J=15.8 Hz), 6.26 (0.5H, d,J=15.8 Hz), 6.59 (1H, d, J=8 Hz), 6.61 (1H, d, J=8 Hz), 7.40 (1H, d, J=8Hz), 7.43 (1H, d, J=8 Hz), 7.68 (0.5H, d, J=15.8 Hz), 7.69 (0.5H, d,J=15.8 Hz); MS (ES+) m/z 343.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 819

(2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.06-2.44 (19H, m), 3.17-3.66 (4H, m),3.78-4.13 (3H, m), 4.87 (1H, m), 6.19 (1H, br), 6.40 (1H, m), 6.61 (1H,d, J=8.5 Hz), 6.64 (1H, d, J=8.5 Hz), 7.28-7.41 (3H, m), 10.99 (1H, s);MS ( ) m/z not detected.

The following compounds were obtained in a similar manner to that ofPreparation 62.

Preparation 820

(2E)-3-(5-chloro-6-{[1-(3-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6): δ 1.50-1.90 (11H, m), 2.05-2.11 (2H, m), 2.73-2.78(2H, m), 3.49 (2H, s), 3.95-4.05 (2H, m), 4.89 (1H, s), 6.30 (1H, d,J=15.9 Hz), 6.52 (1H, d, J=7.8 Hz), 7.02-7.16 (3H, m), 7.32-7.42 (2H,m), 7.84 (1H, s), 8.20 (1H, s), 11.07 (1H, brs),

Mass (ESI): 489(M+H)+.

Preparation 821

(2E)-3-(5-chloro-6-{[1-(3-methyl-2-buten-1-yl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6): δ 1.53-1.85 (18H, m), 1.93-2.20 (2H, m), 2.87-3.07(4H, m), 3.49-0.355 (1H, m), 3.80-4.10 (2H, m), 4.87 (1H, s), 5.17-5.24(1H, m), 6.31 (1H, d, J=15.9 Hz), 6.55 (1H, d, J=7.8 Hz), 7.35 (1H, d,J=15.9 Hz), 7.84 (1H, s), 8.20 (1H, s), 11.08 (1H, brs),

Mass (ESI): 449(M+H)+.

Preparation 822

(2E)-3-(5-chloro-6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 0.78-0.90 (2H, m), 1.14-1.30 (3H, m), 1.46-2.08(20H, m), 2.78-2.83 (2H, m), 3.49-3.55 (1H, m), 3.80-4.05 (2H, m), 4.88(1H, s), 6.30 (1H, d, J=15.9 Hz), 6.49 (1H, d, J=7.8 Hz), 7.35 (1H, d,J=15.9 Hz), 7.83 (1H, s), 8.20 (1H, s), 11.07 (1H, brs).

Mass (ESI) 477(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 370.

Preparation 823

ethyl 6-[(4-methylphenyl)amino]nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.36 (3H, s), 4.35 (2H,q, J=7 Hz), 6.75 (1H, d, J=9 Hz), 6.89 (1H, br-s), 7.15-7.26 (4H, m),8.03 (1H, dd, J=9, 2.5 Hz), 8.82 (1H, d, J=2.5 Hz); MS (ES+) m/z 257.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 824

{6-[(4-methylphenyl)amino]-3-pyridinyl)methanol

¹H-NMR (300 MHz, CDCl₃) δ 2.33 (3H, s), 4.58 (2H, s), 6.54 (1H, br-s),6.82 (1H, d, J=8.5 Hz), 7.11-7.22 (4H, m), 7.52 (1H, dd, J=8.5, 2.5+Hz),8.14 (1H, d, J=2.5 Hz); MS (ES+) m/z 215.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 825

6-[(4-methylphenyl)amino]nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 2.37 (3H, s), 6.79 (1H, d, J=8.5 Hz), 7.15(1H, br-s), 7.18-7.30 (4H, m), 7.94 (1H, dd, J=8.5, 2 Hz), 8.60 (1H, d,J=2 Hz), 9.83 (1H, s); MS (ES+) m/z 213.

The following compound was obtained in a similar manner to that ofPreparation 683.

Preparation 826

(2E)-3-{6-[(4-methylphenyl)amino]-3-pyridinyl}acrylic acid

¹H-NMR (300 MHz, DMSO-d6) δ 2.25 (3H, s), 6.35 (1H, d, J=16 Hz), 6.81(1H, d, J=8.5 Hz), 7.10 (2×1H, d, J=8.5 Hz), 7.51 (1H, d, J=16 Hz), 7.58(2H, d, J=8.5 Hz), 7.93 (1H, dd, J=8.5, 2 Hz), 8.35 (1H, d, J=2 Hz),9.33 (1H, s); MS (ES+) m/z 255.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 827

(2E)-3-{6-[(4-methylphenyl)amino]-3-pyridinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.45-1.78 (6H, m), 2.25 (3H, s), 3.53 (1H,m), 3.96 (1H, m), 4.89 (1H, m), 6.32 (1H, d, J=16 Hz), 6.83 (1H, d,J=8.8 Hz), 7.10 (2H, d, J=8.5 Hz), 7.42 (1H, d, J=16 Hz), 7.57 (2H, d,J=8.5 Hz), 7.76 (1H, br-d, J=8.8 Hz), 8.30 (1H, d, J=1.5 Hz), 9.29 (1H,s), 11.13 (1H, br-s); MS (ES+) m/z 354.

The following compound was obtained in a similar manner to that ofPreparation 674.

Preparation 828

ethyl 6-[(2-ethoxyphenyl)amino]nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7 Hz), 1.46 (3H, t, J=7 Hz),4.12 (2H, q, J=7 Hz), 4.36 (2H, q, J=7 Hz), 6.84 (1H, d, J=8.8 Hz),6.89-7.06 (3H, m), 7.28 (1H, s), 8.03 (1H, dd, J=7.5, 2 Hz), 8.07 (1H,dd, J=8.8, 2.2 Hz), 8.89 (1H, d, J=2.2 Hz); MS (ES+) m/z 287.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 829

{6-[(2-ethoxyphenyl)amino]-3-pyridinyl)methanol

¹H-NMR (300 MHz, CDCl₃) δ 1.45 (3H, t, J=7 Hz), 1.71 (1H, br), 4.11 (2H,q, J=7 Hz), 4.60 (2H, s), 6.86-6.99 (4H, m), 7.05 (1H, s), 7.56 (1H, dd,J=8.5, 2.5 Hz), 7.97 (1H, m), 8.20 (1H, d, J=2.5 Hz); MS (ES+) m/z 245.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 830

(2E)-3-{6-[(2-ethoxyphenyl)amino]-3-pyridinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.35 (3H, t, J=7 Hz), 1.46-1.78 (6H, m),3.53 (1H, m), 3.96 (1H, m), 4.10 (2H, q, J=7 Hz), 4.89 (1H, m), 6.33(1H, d, J=16 Hz), 6.87-7.07 (4H, m), 7.42 (1H, d, J=16 Hz), 7.77 (1H,m), 8.08 (1H, dd, J=8, 1 Hz), 8.29 (1H, d, J=2 Hz), 8.37 (1H, s), 11.13(1H, s); MS (ES+) m/z 384.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 831

6-[(2-ethoxyphenyl)amino]nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 1.46 (3H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz),6.88 (1H, d, J=8.8 Hz), 6.91-7.11 (3H, m), 7.43 (1H, s), 7.97 (1H, dd,J=8.8, 2.2 Hz), 8.09 (1H, dd, J=7.7, 1.8 Hz), 8.66 (1H, d, J=2.2 Hz),9.86 (1H, s); MS (ES+) m/z 243.

The following compound was obtained in a similar manner to that ofPreparation 683.

Preparation 832

(2E)-3-{6-[(2-ethoxyphenyl)amino]-3-pyridinyl}acrylic acid

¹H-NMR (300 MHz, DMSO-d6) δ 1.35 (3H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz),6.37 (1H, d, J=16 Hz), 6.86-7.07 (4H, m), 7.50 (1H, d, J=16 Hz), 7.93(1H, dd, J=8.8, 2.2 Hz), 8.09 (1H, dd, J=8, 1.4 Hz), 8.33 (1H, d, J=2.2Hz), 8.42 (1H, s); MS (ES+) m/z 285.

The following compound was obtained in a similar manner to that ofPreparation 405.

Preparation 833

(2E)-3-(4-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}phenyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d6) δ 0.82-1.03 (2H, m), 1.04-1.32 (3H, m),1.54-2.02 (7H, m), 2.24-2.46 (1H, m), 2.83-3.45 (5H, m), 3.56-4.34 (2H,m), 6.21 (1H, d, J=16 Hz), 6.61 (2H, d, J=8.5 Hz), 6.69 (1H, m), 7.46(2H, d, J=8.5 Hz), 7.46 (1H, d, J=16 Hz), 10.29 (1H, br), 12.00 (1H, s);MS (ES+) m/z 329.

The following compound was obtained in a similar manner to that ofPreparation 363.

Preparation 834

ethyl(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate

¹H-NMR (300 MHz, CDCl₃) δ 0.78-0.96 (2H, m), 1.06-1.40 (5H, m),1.40-1.84 (11H, m), 2.00-2.25 (3H, m), 2.38-2.64 (3H, m), 3.96 (1H, brpeak), 4.25 (2H, q, J=7.1 Hz), 5.49 (1H, br peak), 6.21 (1H, d, J=15.9Hz), 6.39 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=15.9 Hz), 7.61 (1H, dd,J=8.7, 2.4 Hz), 8.19 (1H, d, J=2.2 Hz).

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 835

(2E)-3-(4-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 0.74-0.91 (2H, m), 1.04-1.30 (3H, m), 1.40(1H, m), 1.46-1.81 (12H, m), 2.11-2.29 (3H, m), 2.33 (1H, dd, J=9, 4.5Hz), 2.42 (1H, m), 2.56 (1H, m), 2.75 (1H, dd, J=9, 7 Hz), 3.53 (1H, m),3.82-4.01 (2H, m), 4.87 (1H, m), 6.16 (1H, br-d, J=16 Hz), 6.29 (1H, d,J=6.5 Hz), 6.56 (2H, d, J=8.8 Hz), 7.26-7.38 (3H, m), 10.97 (1H, s); MS(ES+) m/z 428.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 836

[5-chloro-6-(2,3-dihydro-1H-inden-1-ylamino)-3-pyridinyl]methanol

¹H-NMR (300 MHz, CDCl₃) δ 1.62 (1H, t, J=4 Hz), 1.88 (1H, m), 2.72 (1H,m), 2.84-3.10 (2H, m), 4.57 (2H, d, J=4 Hz), 5.25 (1H, br-d, J=8 Hz),5.70 (1H, ddd, J=8, 7.5, 7.5 Hz), 7.17-7.37 (4H, m), 7.57 (1H, d, J=2Hz), 8.05 (1H, d, J=2 Hz); MS (ES+) m/z 275.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 837

5-chloro-6-(2,3-dihydro-1H-inden-1-ylamino)nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 1.94 (H, m), 2.74 (1H, m), 2.85-3.13 (2H, m),5.76-5.92 (2H, m), 7.18-7.38 (4H, m), 7.98 (1H, d, J=2 Hz), 8.51 (1H, d,J=2 Hz), 9.80 (1H, s); MS (ES+) m/z 273.

The following compound was obtained in a similar manner to that ofPreparation 683.

Preparation 838

(2E)-3-[5-chloro-6-(2,3-dihydro-1H-inden-1-ylamino)-3-pyridinyl]acrylicacid

¹H-NMR (300 MHz, CDCl₃) δ 1.92 (1H, m), 2.74 (1H, m), 2.86-3.12 (2H, m),5.58 (1H, d, J=8 Hz), 5.76 (1H, ddd, J=8, 7.5, 7.5 Hz), 6.26 (1H, d,J=15.7 Hz), 7.19-7.40 (4H, m), 7.66 (1H, d, J=15.7 Hz), 7.73 (1H, d,J=1.8 Hz), 8.22 (1H, d, J=1.8 Hz); MS (ES+) m/z 315.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 839

(2E)-3-[5-chloro-6-(2,3-dihydro-1H-inden-1-ylamino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.44-1.76 (1H, m), 2.08 (1H, m), 2.76-3.15(3H, m), 3.53 (1H, m), 3.95 (1H, m), 4.90 (1H, m), 5.78 (1H, ddd, J=8,7.5, 7.5 Hz), 6.35 (1H, d, J=16 Hz), 7.06 (1H, d, J=8.5 Hz), 7.13-7.32(5H, m), 7.40 (1H, d, J=16 Hz), 7.90 (1H, s), 8.26 (1H, s), 11.11 (1H,br-s); MS (ES+) m/z 414.

The following compound was obtained in a similar manner to that ofPreparation 390.

Preparation 840

(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl)acrylicacid

MASS(API-ES); 341 (M+H)+.

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.55-1.86 (1H, m), 2.07-2.73 (4H, m),2.77-2.93 (1H, m), 3.57, 3.64 (2H, ABq, J=13 Hz), 3.90-4.10 (1H, m),5.99 (1H, d, J=5.2 Hz), 6.26 (1H, d, J=16 Hz), 6.67 (1H, t, J=8.8 Hz),7.10-7.37 (7H, m), 7.43 (1H, d, J=16 Hz).

The following compound was obtained in a similar manner to that ofPreparation 397.

Preparation 841

(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

MASS(API-ES); 440 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.39-1.89 (7H, m), 2.07-2.33 (1H, m),2.36-2.70 (3H, m), 2.75-2.93 (1H, m), 3.44-3.70 (3H, m), 3.83-4.12 (2H,m), 4.88 (1H, s), 5.90 (1H, d, J=5.3 Hz), 6.23 (1H, d, J=16 Hz), 6.69(1H, t, J=8.9 Hz), 7.11-7.44 (8H, m).

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 842

ethyl(2E)-3-(5-chloro-6-{[1-(3-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl}acrylate

¹H NMR (DMSO-d6, δ): 1.23(3H, t, J=7.1 Hz), 1.58-1.83(4H, m),2.00-2.11(2H, m), 2.78-2.84(2H, m), 3.50(2H, s), 3.96-4.05(1H, m),4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.63(1H, d, J=8.0 Hz),7.02-7.16(3H, m), 7.32-7.42(1H, m), 7.50(1H, d, J=15.9 Hz), 8.10(1H, d,J=1.9 Hz), 8.27(1H, d, J=1.9 Hz),

Mass (APCI): 418(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 62.

Preparation 843

(2E)-3-(5-chloro-6-{[1-(3-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 1.45-1.90(10H, m), 1.99-2.11(2H, m), 2.78-2.83(2H,m), 3.40-3.60(1H, m), 3.55(2H, s), 3.90-4.10(2H, m), 4.89(1H, brs),6.30(1H, d, J=15.9 Hz), 6.52(1H, d, J=7.9 Hz), 7.25-7.41(5H, m),7.84(1H, s), 8.20(1H, s), 11.07(1H, brs),

Mass (APCI): 505(M+H)+.

Preparation 844

(2E)-3-(5-chloro-6-{[1-(2-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 1.53-1.69(8H, m), 1.79-1.81(2H, m), 2.05-2.12(2H,m), 2.81-2.83(2H, m), 3.50-3.60(1H, m), 3.52(2H, s), 3.92-3.98(2H, m),4.88(1H, s), 6.30(1H, d, J=15.7 Hz), 6.53(1H, d, J=7.9 Hz),7.14-7.20(2H, m), 7.31-7.43(3H, m), 7.83(1H, s), 8.17(1H, s), 11.07(1H,s),

Mass (APCI): 489(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 845

ethyl(2E)-3-(5-chloro-6-{(1-(3-methyl-2-buten-1-yl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 1.25 (3H, t, J=7.4 Hz), 1.61-1.81 (4H, m), 1.61(3H, s), 1.70 (3H, s), 1.91-2.01 (2H, m), 2.81-2.89 (4H, m), 3.87-4.02(1H, m), 4.16 (2H, q, J=7.4 Hz), 5.15-5.22 (1H, m), 6.47 (1H, d, J=15.9Hz), 6.62 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=15.9 Hz), 8.10 (1H, d, J=1.9Hz), 8.27 (1H, d, J=1.9 Hz),

Mass (ESI): 378(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 414.

Preparation 846

(2E)-3-(5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H-NMR (300 MHz, CDCl₃) δ 1.50-1.95 (10H, m), 2.50-2.62 (4H, m), 3.67(1H, m), 3.71 (2H, s), 3.97 (1H, m), 5.00 (1H, m), 6.30 (1H, br), 6.97(1H, ddd, J=7.5, 7.5, 1 Hz), 7.15 (1H, dd, J=7.5, 1 Hz), 7.31 (1H, dd,J=7.5, 7.5 Hz), 7.64 (1H, d, J=15.5 Hz), 7.74 (1H, d, J=2 Hz), 8.24 (1H,d, J=2 Hz), 8.34 (1H, d, J=7.5 Hz), 8.36 (1H, br), 10.95 (1H, s);

MS ( ) m/z not detected.

The following compound was obtained in a similar manner to that ofPreparation 62.

Preparation 847

(2E)-3-(5-chloro-6-{[1-(3-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 1.53-1.84(10H, m), 1.99-2.11(2H, m), 2.78-2.84(2H,m), 3.45-3.55(1H, m), 3.50(2H, s), 3.85-4.10(2H, m), 4.88(1H, brs),6.30(1H, d, J=15.9 Hz), 6.52(1H, d, J=7.9 Hz), 7.32-7.39(2H, m),7.68-7.72(1H, m), 7.84(1H, s), 8.20(1H, s), 8.45-8.50(2H, m), 11.07(1H,brs),

Mass (APCI): 472(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 848

ethyl(2E)-3-(5-chloro-6-{[1-(2-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl}acrylate

¹H NMR (DMSO-d6, δ): 1.24(3H, t, J=7.1 Hz), 1.61-1.78(4H, m),2.03-2.13(2H, m), 2.80-2.86(2H, m), 3.53(2H, s), 3.93-4.05(1H, m),4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.62(1H, d, J=8.0 Hz),7.15-7.44(4H, m), 7.50(1H, d, J=15.9 Hz), 8.09(1H, d, J=1.9 Hz),8.27(1H, d, J=1.9 Hz),

Mass (APCI) 418(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 62.

Preparation 849

(2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide

¹H NMR (DMSO-d6, δ): 1.53-1.85(10H, m), 2.03-2.14(2H, m), 2.77-2.83(2H,m), 3.50-3.54(1H, m), 3.51(2H, s), 3.90-4.10(2H, m), 4.88(1H, brs),6.31(1H, d, J=15.3 Hz), 6.53(1H, d, J=7.9 Hz), 7.31(2H, d, J=5.9 Hz),7.35(1H, d, J=15.9 Hz), 7.84(1H, s), 8.20(1H, s), 8.51(2H, d, J=5.9 Hz),11.07(1H, brs),

Mass (APCI): 472(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 198.

Preparation 850

ethyl(2E)-3-(5-chloro-6-{[1-(3-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate

¹H NMR (DMSO-d6, δ): 1.24(3H, t, J=7.1 Hz), 1.55-1.83(4H, m),2.01-2.11(2H, m), 2.77-2.84(2H, m), 3.50(2H, s), 3.90-4.05(1H, m),4.16(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.63(1H, d, J=7.9 Hz),7.33-7.39(1H, m), 7.50(1H, d, J=15.9 Hz), 7.68-7.73(1H, m), 8.09(1H, d,J=1.9 Hz), 8.27(1H, d, J=1.9 Hz), 8.45-8.50(2H, m),

Mass (APCI): 401(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 683.

Preparation 851

(2E)-3-(5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}-3-pyridinyl)acrylicacid

¹H-NMR (300 MHz, DMSO-d6) δ 1.72-1.86 (4H, m), 2.44-2.58 (4H, m), 3.73(2H, s), 6.52 (1H, d, J=16 Hz), 6.98 (1H, dd, J=7.5, 7.5 Hz), 7.23 (1H,d, J=7.5 Hz), 7.29 (1H, dd, J=7.5, 7.5 Hz), 7.52 (1H, d, J=7.5 Hz), 8.28(1H, d, J=2 Hz), 8.33 (1H, d, J=7.5 Hz), 8.39 (1H, d, J=2 Hz), 10.97(1H, s); MS (ES+) m/z 358.

The following compound was obtained in a similar manner to that ofPreparation 361.

Preparation 852

(5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}-3-pyridinyl)methanol

¹H-NMR (300 MHz, CDCl₃) 1.77-1.88 (4H, m), 2.50-2.60 (4H, m), 3.70 (2H,s), 4.59 (2H, s), 6.92 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.14 (1H, dd,J=7.5, 1.5 Hz), 7.30 (1H, m), 7.64 (1H, d, J=2 Hz), 8.07 (1H, d, J=2′Hz), 8.32 (1H, d, J=7.5 Hz), 10.56 (1H, s); MS (ES+) m/z 318.

The following compound was obtained in a similar manner to that ofPreparation 382.

Preparation 853

5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}nicotinaldehyde

¹H-NMR (300 MHz, CDCl₃) δ 1.76“1.91 (4H, m), 2.49-2.62 (4H, m), 3.74(2H, s), 7.04 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.18 (1H, d, J=7.5 Hz),7.35 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 8.03 (1H, d, J=2 Hz), 8.38 (1H, d,J=7.5 Hz), 8.52 (1H, d, J=2 Hz), 9.82 (1H, s), 11.39 (1H, br-s); MS(ES+) m/z 316.

The following compound was obtained in a similar manner to that ofPreparation 714.

Preparation 854

ethyl(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl)acrylate

MASS(API-ES); 369 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.63-1.87 (1H,m), 2.08-2.33 (1H, m), 2.37-2.70 (3H, m), 2.75-2.90 (1H, m), 3.55, 3.62(2H, ABq, J=13 Hz), 3.88-4.11 (1H, m), 4.15 (2H, q, J=7.1 Hz), 6.02 (1H,d, J=5.1 Hz), 6.34 (1H, d, J=16 Hz), 6.67 (1H, t, J=8.8 Hz), 7.16-7.37(6H, m), 7.41-7.59 (2H, m).

The following compound was obtained in a similar manner to that ofPreparation 380.

Preparation 855

(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl)methanol

MASS(API-ES); 301 (M+H)+,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.52-1.86 (1H, m), 2.05-2.31 (1H, m),2.32-2.69 (3H, m), 2.71-2.88 (1H, m), 3.46-3.68 (2H, m), 3.81-4.05 (1H,m), 4.32 (2H, d, J=5.6 Hz), 4.98 (1H, t, J=5.6 Hz), 5.15 (1H, d, J=5.7Hz), 6.62 (1H, t, J=8.7 Hz), 6.84-7.00 (2H, m), 7.15-7.40 (5H, m).

The following compounds were obtained in a similar manner to that ofPreparation 379.

Preparation 856

methyl 4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorobenzoate

MASS(API-ES); 329 (M+H)+

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.64-1.94 (1H, m), 2.06-2.35 (1H, m),2.38-2.95 (4H, m), 3.55, 3.63 (2H, ABq, J=13 Hz), 3.76 (3H, s),3.92-4.14 (1H, m), 6.30 (1H, d, J=6.8 Hz), 6.74 (1H, t, J=8.7 Hz)7.16-7.38 (5H, m), 7.49 (1H, dd, J=1.9 Hz, J=13 Hz), 7.60 (1H, dd, J=1.9Hz, J=8.7 Hz).

The following compounds were obtained in a similar manner to that ofPreparation 703.

Preparation 857

tert-butyl (3R)-3 ({4 [(1E)-3-ethoxy-3-oxo-1-propen-1-ylphenyl]amino}-1-pyrrolidinecarboxylate

¹H-NMR (300 MHz; CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.47 (9H, s), 1.92 (1H,m), 2.20 (1H, m), 3.26 (1H, m), 3.38-3.86 (2H, m), 3.71 (1H, m),4.00-4.12 (2H, m), 4.24 (2H, q, J=7 Hz), 6.23 (1H, d J=16 Hz), 6.57 (2H,d, J=8.5 Hz), 7.38 (2H, d, J=8.5 Hz), 7.60 (1H, d, J=16 Hz).

Preparation 858

ethyl (2E)-3-{4-[(6-methyl-2-pyridinyl)amino]phenyl}acrylate

¹H-NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7 Hz), 2.47 (3H, s), 4.26 (2H,q, J=7 Hz), 6.34 (1H, d, J=15.7 Hz), 6.64 (1H, s), 6.68 (1H, d, J=7.5Hz), 6.76 (1H, d, J=7.5 Hz), 7.37 (2H, d, J=9 Hz), 7.45 (1H, dd, J=7.5,7.5 Hz), 7.48 (2H, d, J=9-Hz), 7.64 (1H, d, J=15.7 Hz); MS (ES+) m/z283.

Preparation 859

To a stirred solution of ethyl(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate25 (384 mg) in acetonitrile (5 mL) was added di-tert-butyl dicarbonate(468 mg) and 4-dimethylaminopyridine (26 mg), and the mixture wasstirred at 80° C. for 18 hours. Additional di-tert-butyl dicarbonate(1.0 g) and 4-dimethylaminopyridine (50 mg) was added and the mixturewas stirred at 80° C. for 24 hours. The solvent was evaporated in vacuoand the residue was purified by silica gel column chromatography(chloroform/methanol=90/10 v/v) to give ethyl(2E)-3-(2-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate(330 mg) as a tan solid.

¹H-NMR (300 MHz, CDCl₃) δ 0.66-0.86 (2H, m), 1.04-1.72 (9H, m), 1.35(3×3H, t, J=7 Hz), 1.46 (9H, s), 2.06-2.30 (4H, m), 2.54 (2H, t, J=7Hz), 2.70 (1H, dd, J=9, 7 Hz), 2.84 (1H, dd, J=9, 8 Hz), 4.29 (2H, q,J=7 Hz), 4.96 (1H, m), 6.54 (1H, d, J=16 Hz), 7.59 (1H, d, J=16 Hz),8.80 (2×1H, s); MS (ES+) M/z 459.

Preparation 860

To a solution of ethyl(2E)-3-[5-chloro-6-(4-piperidinylamino)-3-pyridinyl]acrylatedihydrochloride (500 mg) in DMF (5 ml) was added1-chloro-3-(chloromethyl)benzene (0.173 ml) andN,N-diisopropylethylamine (0.91 ml), the mixture was stirred at 70° C.for 7 hour. The mixed solution was poured into a mixture of water (30ml) and AcOEt (30 ml). The organic layer was separated, washed withwater twice and brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatographyeluted with 5% MeOH in dichloromethane to give ethyl(2E)-3-(5-chloro-6-{[1-(3-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate(261 mg, 46%).

¹H NMR (DMSO-d6, δ): 1.23(3H, t, J=7.1 Hz), 1.62-1.83(2H, m),1.99-2.11(2H, m), 2.78-2.83(2H, m), 3.48(2H, s), 3.90-4.10(1H, m),4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.62(1H, d, J=7.9 Hz),7.25-7.40(4H, m), 7.50(1H, d, J=15.9 Hz), 8.09(1H, d, J=1.9 Hz),8.27(1H, d, J=1.9 Hz).

Mass (APCI): 434(M+H)+.

The following compound was obtained in a similar manner to that ofPreparation 860.

Preparation 861

ethyl(2E)-3-(5-chloro-6-{[1-(2-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl}acrylate

¹H NMR (DMSO-d6, δ): 1.24(3H, t, J=7.1 Hz), 1.59-1.84(4H, m),2.09-2.20(2H, m), 2.52-2.88(2H, m), 3.56(2H, s), 3.90-4.15(1H, m),4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.65(1H, d, J=7.9 Hz),7.24-7.55(4H, m), 7.50(1H, d, J=15.9 Hz), 8.10(1H, d, J=1.9 Hz),8.28(1H, d, J=1.9 Hz).

Mass (APCI): 434(M+H)+.

Preparation 862

To a solution of ethyl(2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate(308 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOHaq (2.3 ml), themixture was stirred at 80° C. for 1 hour. The pH of the mixture wasadjusted to ca.4.5 with 1N HClaq. The solution was evaporated underreduced pressure to give crude(2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid (469 mg, 164%)

¹H NMR (DMSO-d6, δ): 1.59-1.87(4H, m), 2.03-2.14(2H, m), 2.77-2.83(2H,m), 3.51(2H, s), 3.94-4.03(1H, m), 6.38(1H, d, J=15.7 Hz), 6.48(1H, d,J=7.9 Hz), 7.31(1H, d, J=15.7 Hz), 7.32(2H, d, J=5.9 Hz), 7.98(1H, d,J=2.0 Hz), 8.19(1H, d, J=2.0 Hz), 8.51(2H, d, J=5.9 Hz),

Mass (APCI): 373(M+H)+.

The following compounds were obtained in a similar manner to that ofPreparation 862.

Preparation 863

(2E)-3-(5-chloro-6-{[1-(2-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.58-1.85(4H, m), 2.07-2.18(2H, m), 2.81-2.86(2H,m), 3.59(2H, s), 3.87-4.02(1H, m), 6.34(1H, d, J=15.7 Hz), 6.39(1H, d,J=7.3 Hz), 7.21(1H, d, J=15.7 Hz), 7.23-7.29(1H, m), 7.43(1H, d, J=7.8Hz), 7.73-7.82(1H, m), 7.92(1H, d, J=2.0 Hz), 8.15(1H, d, J=2.0 Hz),8.48-8.50(1H, m),

Mass (APCI): 373(M+H)+.

Preparation 864

(2E)-3-(5-chloro-6-{[1-(2-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.80-2.10 (4H, m), 2.60-3.20 (4H, m), 3.16 (2H, s),6.40 (1H, d, J=15.9 Hz), 6.79 (1H, brs), 7.23-7.71 (5H, m), 8.07 (1H, d,J=1.9 Hz), 8.25 (1H, d, J=1.9 Hz),

Mass (ESI): 390(M+H)+.

Preparation 865

(2E)-3-(5-chloro-6-{[1-(3-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.55-1.86(4H, m), 2.01-2.11(2H, m), 2.78-2.83(2H,m), 3.50(2H, s), 3.88-4.02(1H, m), 6.38(1H, d, J=15.7 Hz), 8.44(1H, d,J=7.9 Hz), 7.28(1H, d, J=15.7 Hz), 7.35-7.39(1H, m), 7.69-7.73(1H, m),7.95(1H, d, J=2.0 Hz), 8.18(1H, d, J=2.0 Hz), 8.45-8.50(2H, m),

Mass (APCI): 373(M+H)+.

Preparation 866

(2E)-3-(5-chloro-6-{[1-(3-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.57-1.89(4H, m), 2.01-2.11(2H, m), 2.78-2.83(2H,m), 3.48(2H, s), 3.85-4.10(1H, m), 6.37(1H, d, J=15.9 Hz), 6.51(1H, 6,J=7.9 Hz), 7.11-7.40(5H, m), 8.21(1H, d, J=1.9 Hz), 8.62(1H, d, J=1.9Hz),

Mass (APCI): 406(M+H)+.

Preparation 867

(2E)-3-(5-chloro-6-{[1-(3-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.23-1.43 (2H, m), 1.64-1.67 (2H, m), 1.95-2.06(2H, m), 2.73-2.79 (2H, m), 3.16 (2H, s), 3.65-3.75 (1H, m), 5.58 (1H,d, J=15.9 Hz), 6.85 (1H, d, J=15.9 Hz), 7.01-7.17 (4H, m), 7.30-7.41(1H, m), 7.44 (1H, d, J=1.9 Hz),

Mass (ESI): 390(M+H)+.

Preparation 868

(2E)-3-(5-chloro-6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

Mass (APCI): 378(M+H)+.

Preparation 869

(2E)-3-(5-chloro-6-{[1-(3-methyl-2-buten-1-yl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.56-1.90 (2H, m), 1.62 (3H, s), 1.70 (3H, s),1.96-2.06 (2H, m), 2.83-2.93 (4H, m), 3.87-4.02 (1H, m), 5.16-5.23 (1H,m), 6.37 (1H, d, J=15.9 Hz), 6.55 (1H, d, J=7.9 Hz), 7.40 (1H, d, J=15.9Hz), 8.03 (1H, d, J=1.9 Hz), 8.22 (1H, d, J=1.9 Hz),

Mass (ESI): 350(M+H)+.

Preparation 870

(2E)-3-(5-chloro-6-{[1-(2-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylicacid

¹H NMR (DMSO-d6, δ): 1.59-1.91(4H, m), 2.10-2.20(2H, m), 2.82-2.88(2H,m), 3.57(2H, s), 3.97-4.06(1H, m), 6.38(1H, d, J=15.9 Hz), 6.56(1H, d,J=7.9 Hz), 7.26-7.52(5H, m), 8.03(1H, d, J=1.9 Hz), 8.23(1H, d, J=1.9Hz),

Mass (APCI): 406(M+H)+.

Preparation 871

Palladium(II) acetate (25 mg) and2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (106 mg) in dioxane (10mL) was stirred at ambient temperature for 15 minutes. To thissuspension was added ethyl 5,6-dichloronicotinate (500 mg),2-aminoindane (363 mg), and cesium carbonate (1.1 g), and the mixturewas heated at 100° C. for 8 hours. The resulting mixture was allowed tocool to ambient temperature, poured into water, and extracted with ethylacetate. The organic phase was washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=10/1 v/v) to giveethyl 5-chloro-6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (420 mg) asa pale tan solid.

¹H-NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.86 (2H, dd, J=16, 5Hz), 3.43 (2H, dd, J=16, 7 Hz), 4.27 (2H, q, J=7 Hz), 4.99 (1H, m), 5.59(1H, br-d, J=3 Hz), 7.17-7.25 (4H, m), 8.02 (1H, d, J=2 Hz), 8.73 (1H,d, J=2 Hz); MS (ES+) m/z 317.

The following compounds were obtained in a similar manner to that ofPreparation 871.

Preparation 872

ethyl 5-chloro-6-[(4-methylphenyl)amino]nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.35 (3H, s), 4.35 (2H,q, J=7 Hz), 7.19 (2H, d, J=8.5 Hz), 7.20 (1H, s), 7.50 (2H, d, J=8.5Hz), 8.14 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz); MS (ES+) m/z 291.

Preparation 873

ethyl 5-chloro-6-[(2-ethoxyphenyl)amino]nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7 Hz), 1.51 (3H, t, J=7 Hz),4.16 (2H, q, J=7 Hz), 4.36 (2H, q, J=7 Hz), 6.92 (1H, m), 6.98-7.05 (2H,m), 8.15 (1H, d, J=2 Hz), 8.27 (1H, br-s), 8.66 (1H, m), 8.82 (1H, d,J=2 Hz); MS (ES+) m/z 321.

Preparation 874

ethyl 5-chloro-6-(2,3-dihydro-1H-inden-1-ylamino)nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.92 (1H, m), 2.74 (1H,m), 2.87-3.12 (2H, m), 4.35 (2H, q, J=7 Hz), 5.63 (1H, br-d, J=8 Hz),5.80 (1H, ddd, J=8, 7.5, 7.5 Hz), 7.19-7.36 (4H, m), 8.06 (1H, d, J=2Hz), 8.75 (1H, d, J=2 Hz); MS (ES+) m/z 317.

Preparation 875

ethyl 5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}nicotinate

¹H-NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7 Hz), 1.78-1.88 (4H, m),2.51-2.62 (4H, m), 3.72 (2H, s), 4.36 (2H, q, J=7 Hz), 6.99 (1H, ddd,J=7.5, 7.5, 1.5 Hz), 7.16 (1H, dd, J=7.5, 1.5 Hz), 7.32 (1H, ddd, J=7.5,7.5, 1.5 Hz), 8.12 (1H, d, J=2 Hz), 8.36 (1H, dd, J=7.5, 1.5 Hz), 8.76(1H, d, J=2 Hz), 11.07 (1H, s); MS (ES+) m/z 360.

Preparation 876

A mixture of ethyl 1-(2-nitrobenzyl)pyrrolidine (1.90 g) and 10%palladium on carbon (200 mg) in methanol (40 mL) was hydrogenated atambient temperature. After completion of the reaction, the catalyst inthe reaction mixture was removed by filtration. The solvent wasevaporated in vacuo. The residue was purified by silica gel columnchromatography (chloroform/methanol=20/1 v/v) to give[2-(1-pyrrolidinylmethyl)phenyl]amine (1.65 g) as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) δ 1.72-1.87 (4H, m), 2.46-2.62 (4H, m), 3.65(2H, s), 6.61-6.72 (2H, m), 7.01 (1H, br-d, J=8 Hz), 7.09 (1H, br-dd,J=8, 8 Hz); MS (ES+) m/z 177.

Preparation 877

To a solution of 5,6-dichloronicotinic acid (7.0 g, 35 mmol) in DMF wereadded iodoethane (6.0 g, 38.5 mmol) and K₂CO₃ (5.8 g, 42 mmol) atambient temperature and the mixture was stirred at 45° C. for 5 hrs. Tothe reaction mixture were added (3R)-1-benzyl-3-piperidinaminedihydrochloride (10.1 g, 38.5 mmol) and K₂CO₃ (16.9 g, 122 mmol) and thereaction mixture was stirred at 90° C. for 18 hrs. The reaction mixturewas evaporated in vacuo and the residue was partitioned between waterand EtOAc. The organic layer was separated, washed water and brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc-hexane/1-4˜1-3) togive ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate(6.75 g, 52%) as a powder.

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7.1 Hz), 1.51-1.69 (2H, m),1.69-1.88 (2H, m), 2.18-2.33 (1H, m), 2.41-2.54 (1H, m), 2.54-2.67 (1H,m), 2.67-2.79 (1H, m), 3.45 (1H, d, J=13 Hz), 3.61 (1H, d, J=13 Hz),4.32 (2H, q, J=7.1 Hz), 6.24 (1H, br peak), 7.21-7.41 (5H, m), 8.00 (1H,d, J=2 Hz), 8.65 (1H, d, J=2 Hz); MS (ES+) m/z 374.

EXAMPLE 1

A solution of 10% HCl-MeOH solution (0.75 ml) was added to a mixture of(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(170 mg) in MeOH 3 ml) and stirred at 15-25% for 2 hours. The reactionmixture was evaporated in vacuo and the residue was triturated withsmall amount MeOH and acetone and the precipitate was collected byfiltration to give(2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-hydroxyacrylamidedihydrochloride (107 mg)

NMR (DMSO-d6, δ): 2.04-2.40 (2H, m), 3.18-3.83 (4H, m), 4.43-4.58 (2H,m), 4.80 (1H, m), 6.42 (1H, d, J=15.80 Hz), 7.04 (1H, d, J=9.20 Hz),7.25 (1H, d, J=9.20H), 7.40-7.46 (4H, m), 7.65-7.70 (2H, m), 8.01-8.10(1H, m), 8.18 (1H, s), 11043-11.78 (1H m)

The following compounds were obtained according to a similar manner tothat of Example 1.

EXAMPLE 2

(2E)-3-{6-[(1-Benzyl-3-pyrrolidinyl)(methyl)amino]-3-pyridyl}-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.09-2.40 (2H, m), 3.10 (3H, s), 3.10-3.28 (2H, m),3.46-3.63 (2H, m), 4.41-4.49 (2H, m), 5.24-5.51 (1H, m), 6.38-6.50 (1H,m), 7.03-7.19 (1H, m), 7.38-7.47 (4H, m), 7.64-7.69 (2H, m), 7.98-8.07(1H, m), 8.26 (1H, s)

EXAMPLE 3

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.99-2.50 (2H, m), 3.25-3.83 (4H, m), 4.43, 4.55 (2H,ABq, J=5.38 Hz), 4.77 (1H, m), 6.36-6.45 (1H, m), 6.99 (0.5H, d, J=9.00Hz), 7.19 (0.5H d, J=9.00 Hz), 7.74-7.46 (4H, m), 7.63-7.66 (2H, m),7.98-8.06 (1H, m), 8.18 (1H, s)

EXAMPLE 4

(2E)-3-(6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.06-2.62 (2H, m), 3.26-3.83 (4H, m), 4.44, 4.56 (2H,ABq, J=5.48 Hz), 4.79 (1H, m), 6.42 (1H, d, J=15.72 Hz), 7.02 (0.5H, d,J=9.16 Hz), 7.22 (0.5H, d, J=9.16 Hz), 7.40-7.46 (4H, m), 7.64-7.70 (2H,m), 8.00-8.08 (1H, m), 8.18 (1H, s)

EXAMPLE 5

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.91-2.16 (1H, m), 2.30-2.40 (1H, m), 3.08-3.68 (4H,m), 4.41 (2H, d, J=5.56 Hz), 4.70-4.89 (1H, m), 6.38 (1H, d, J=15.82Hz), 7.34 (1H, d, J=15.82 Hz), 7.30-7.46 (3H, m), 7.62-7.66 (2H, m),7.91 (1H, s), 8.21 (1H, s)

EXAMPLE 6

L(2E)-3-(6-{([(3S)-1-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.16 (2H, m), 3.06-3.70 (4H, m), 4.41 (2H, d,J=5.50 Hz), 4.70-4.89 (1H, m), 6.39 (1H, d, J=15.82 Hz), 7.35 (1H, d,J=15.82 Hz), 7.39-7.51 (4H, m), 7.62-7.66 (2H, m), 7.91 (1H, s), 8.21(1H, s)

EXAMPLE 7

(2E)-N-Hydroxy-3-(6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.80 (2H, m), 3.10-3.90 (4H, m), 3.77 (3H, s),4.30-4.49 (2H, m), 4.50-4.90 (1H, m), 6.40 (1H, dd, J=3.0 Hz, J=16 Hz),6.90-7.21 (3H, m), 7.35-7.62 (3H, m), 7.95-8.08 (1H, m), 8.18 (1H, s),8.70-10.40 (1H, m), 11.10-11.60 (1H, m)

MASS(API-ES); 369 (M+H)+Free

EXAMPLE 8

(2E)-3-(6-{[(3R)-1-(4-Fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.90 (2H, m), 3.10-3.90 (4H, m), 4.40-4.90 (3H,m), 6.40 (1H, dd, J=2.5 Hz, J=16 Hz), 6.90-7.35 (3H, m), 7.42 (1H, dd,J=2.5 Hz, J=16 Hz), 7.60-7.80 (2H, m), 7.90-8.10 (1H, m), 8.18 (1H, s),8.70-10.40 (1H, m), 11.30-11.80 (1H, m)

MASS(API-ES); 357 (M+H)+Free

EXAMPLE 9

(2E)-3-(6-{[(3R)-1-(4-Chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.90-2.80 (2H, m), 3.10-3.90 (4H, m), 4.35-4.85 (3H,m), 6.40 (1H, dd, J=2.0 Hz, J=16 Hz), 6.95-7.25 (1H, m), 7.44 (1H, dd,J=2.0 Hz, J=16 Hz), 7.48-7.60 (2H, m), 7.64-7.80 (2H, m), 7.95-8.10 (1H,m), 8.18 (1H, s), 8.80-10.40 (1H, m), 11.40-11.80 (1H, m)

MASS(API-ES); 373 (M+H)+, 375 (M+H+2)+Free

EXAMPLE 10

(2E)-N-Hydroxy-3-(6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidedihydrochloride

MASS(API-ES); 353 (M+H)+Free

NMR (DMSO-d6, δ): 1.95-2.75 (2H, m), 2.32 (3H, s), 3.10-3.90 (4H, m),4.25-4.90 (3H, m), 6.40 (1H, dd, J=2.8 Hz, J=16 Hz), 6.95-7.30 (3H, m),7.43 (1H, dd, J=2.5 Hz, J=16 Hz), 7.47-7.60 (2H, m), 7.95-8.10 (1H, m),8.18 (1H, s), 8.80-10.30 (1H, m), 11.20-11.70 (1H, m)

EXAMPLE 11

(2E)-3-(6-{[(3R)-1-(Cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 0.30-0.70 (4H, m), 1.00-1.30(1H, m), 1.95-2.80 (2H,m), 3.00-4.10 (6H, m), 4.55-4.90 (1H, m), 6.44 (1H, d, J=16 Hz),7.05-7.30 (1H, m), 7.45 (1H, d, J=16 Hz), 8.07 (1H, d, J=9.3 Hz), 8.20(1H, s), 9.20-10.60 (1H, m), 11.00-11.40 (1H, m)

MASS(API-ES); 303 (M+H)+Free

EXAMPLE 12

(2E)-3-(6-{[(3R)-1-Benzoyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.90-2.40 (2H, m), 3.20-4.00 (4H, m), 4.40-4.80 (1H,m), 6.25-6.42 (1H, m), 7.04 (1H, br), 7.25-7.60 (6H, m), 7.85-8.00 (1H,m), 8.10-8.30 (1H, m)

MASS(API-ES); 387 (M+H)+Free, 389

EXAMPLE 13

(2E)-3-(5-Chloro-6-{[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 0.60-0.80 (4H, m), 1.60-1.85 (1H, m), 1.90-2.40 (2H,m), 3.20-4.10 (4H, m), 4.45-5.00 (1H, m), 6.35 (1H, d, J=16 Hz), 7.01(1H, br), 7.35 (1H, d, J=16 Hz), 7.91 (1H, s), 8.23 (1H, s)

MASS(API-ES); 351 (M+H)+Free

EXAMPLE 14

(2E)-3-{6-[(1-Benzoyl-4-piperidyl)amino]-3-pyridyl}-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.30-1.60(2H, m), 1.85-2.10(2H, m), 2.90-4.50(5H, m),6.40(1H, d, J=16.0 Hz), 7.13(1H, d, J=9.0 Hz), 7.38-7.49(6H, m),7.05(1H, d, J=9.0 Hz), 8.16(1H, s), 9.26(1H, brs)

EXAMPLE 15

(2E)-3-(6-{[1-(4-Fluorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.45-1.60(2H, m), 1.95-2.10(2H, m), 3.00-4.60(5H, m),6.39(1H, d, J=16.0 Hz), 7.13(1H, d, J=8.9 Hz), 7.25-7.53(5H, m),8.06(1H, d, J=8.9 Hz), 8.17(1H, s)

Mass (ESI): 385(M+H)+

EXAMPLE 16

(2E)-N-Hydroxy-3-(6-{[1-(4-methylbenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylamidehydrochloride

NMR (DMSO-d6, δ): 1.40-1.60(2H, m), 1.85-2.10(2H, m), 2.34(3H, s),3.00-4.50(5H, m), 6.39(1H, d, J=16.0 Hz), 7.10(1H, d, J=8.9 Hz),7.25(1H, d, J=8.8 Hz), 7.31(1H, d, J=8.8 Hz), 7.44(1H, d, J=16.0 Hz),8.05(1H, d, J=8.9 Hz), 8.16(1H, s)

Mass (ESI): 381(M+H)+

EXAMPLE 17

(2E)-N-Hydroxy-3-(6-{[1-(4-methoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylamidehydrochloride

NMR (DMSO-d6, δ): 1.30-1.60(2H, m), 1.95-2.10(2H, m), 3.15-3.80(4H, m),3.79(3H, s), 3.90-4.15(2H, m), 6.38(1H, d, J=16.0 Hz), 6.99(2H, d, J=8.8Hz), 7.10(1H, d, J=8.9 Hz), 7.38(2H, d, J=8.8 Hz), 7.44(1H, d, J=16.0Hz), 8.04(1H, d, J=8.9 Hz), 8.17(1H, s)

Mass (ESI): 397(M+H)+

EXAMPLE 18

(2E)-N-Hydroxy-3-[6-({1-[4-(1H-pyrrol-1-yl)benzoyl]-4-piperidyl}amino-3-pyridyl]acrylamidehydrochloride

NMR (DMSO-d6, δ): 1.35-1.60(2H, m), 1.85-2.15(2H, m), 3.00-4.50(5H, m),6.28-6.30(2H, m), 6.40(1H, d, J=16.0 Hz), 7.15(1H, d, J=9.5 Hz),7.42-7.53(5H, m), 7.67(2H, d, J=8.6 Hz), 8.07(1H, d, J=9.5 Hz), 8.17(1H,s), 9.30(1H, brs)

Mass (ESI): 432(M+H)+

EXAMPLE 19

N-(4-Chlorophenyl)-4-({5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxamidehydrochloride

NMR (DMSO-d6, δ): 1.40-1.45(2H, m), 1.90-2.10(2H, m), 2.94-3.01(2H, m),3.99(1H, brs), 4.10-4.15(2H, m), 6.37-6.40(1H, m), 7.00-7.14(1H, m),7.27(2H, d, J=8.8 Hz), 7.43-7.53(3H, m), 8.03(1H, m), 8.18(1H, s),8.76(1H, s), 10.81(1H, brs)

Mass (ESI): 416(M+H)+

EXAMPLE 20

4-({5-[(1E)-3-(Hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-N-(4-methylphenyl)-1-piperidinecarboxamidehydrochloride

NMR (DMSO-d6, δ): 1.30-1.60(2H, m), 1.90-2.05(2H, m), 2.23(3H, s),2.85-3.10(2H, m), 4.00-4.25(3H, m), 6.40(1H, d, J=15.4 Hz), 7.04(2H, d,J=8.8 Hz), 7.11(1H, brs), 7.34(2H, d, J=8.8 Hz), 7.45(1H, d, J=15.4 Hz),8.04(1H, d, J=9.6 Hz), 8.17(1H, s), 8.51(1H, s)

Mass (ESI): 396(M+H)+

EXAMPLE 21

4-({5-[(1E)-3-(Hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-N-(4-methoxyphenyl)-1-piperidinecarboxamidehydrochloride

NMR (DMSO-d6, δ): 1.30-1.60(2H, m), 1.90-2.05(2H, m), 2.85-3.10(2H, m),3.70(3H, s), 4.00-4.25(3H, m), 6.41(1H, d, J=15.4 Hz), 6.82(2H, d, J=8.8Hz), 7.15(1H, d, J=9.4 Hz), 7.34(2H, d, J=8.8 Hz), 7.46(1H, d, J=15.4Hz), 8.06(1H, d, J=9.4 Hz), 8.17(1H, s), 8.46(1H, s)

Mass (ESI): 412(M+H)+

EXAMPLE 22

(2E)-3-{6-[(1-Benzoyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.50-2.10(6H, m), 2.80-3.00(2H, m), 6.33(1H, d, J=16.0Hz), 7.25-7.60(6H, m), 7.92(1H, s), 8.20(1H, s)

EXAMPLE 23

(2E)-3-(5-Chloro-6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.50-2.10(6H, m), 2.80-3.10(2H, m), 6.31(1H, d, J=16.0Hz), 6.77(1H, brs), 7.34(1H, d, J=16.0 Hz), 7.42(2H, d, J=8.8 Hz),7.54(2H, d, J=8.8 Hz), 7.91(1H, s), 8.19(1H, s)

EXAMPLE 24

(2E)-3-(5-Chloro-6-{[1-(3-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

¹H NMR (DMSO-d6, δ): 1.45-2.10(4H, m), 2.70-3.30(2H, m), 3.40-3.70(1H,m), 6.35(1H, d, J=16.0 Hz), 6.89(1H, brs), 7.31-7.57(5H, m), 7.95(1H,s), 8.20(1H, s)

EXAMPLE 25

(2E)-3-(5-Chloro-6-{[1-(2-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl]-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.45-2.05(4H, m), 2.80-3.40(3H, m), 4.10-4.30(1H,brs), 4.30-4.70(1H, m), 6.35(1H, d, J=16.0 Hz), 6.80-7.20(1H, m),7.31-7.57(5H, m), 7.96(1H, s), 8.19(1H, s)

EXAMPLE 26

(2E)-3-(5-Chloro-6-{[1-(4-phenoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.45-2.05(4H, m), 2.70-3.30(2H, m), 3.50-3.90(1H, m),4.20-4.70(2H, m), 6.36(1H, d, J=16.0 Hz), 7.01-7.48(11H, m), 7.97(1H,s), 8.20(1H, s)

Mass (ESI): 493(M+H)+

EXAMPLE 27

4-({3-Chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-N-(4-chlorophenyl)-1-piperidinecarboxamidehydrochloride

NMR (DMSO-d6, δ): 1.45-1.75(2H, m), 1.75-1.95(2H, m), 2.83-2.98(2H, m),4.12-4.40(3H, m), 6.36(1H, d, J=15.8 Hz), 7.06(1H, brs), 7.28(2H, d,J=8.8 Hz), 7.3.6(1H, d, J=15.8 Hz), 7.53(2H, d, J=8.8 Hz), 7.58(1H, s),8.21(1H, s), 8.76(1H, s)

Mass (ESII): 450(M+H)+

EXAMPLE 28

(2E)-3-(5-Chloro-6-{[1-(4-chlorobenzyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.20(4H, m), 2.95-3.45(4H, m), 4.27(2H, m),6.33(1H, brs), 7.03(1H, d, J=16.0 Hz), 7.34(1H, d, J=16.0 Hz), 7.54(1H,d, J=8.8 Hz), 7.71(1H, d, J=8.8 Hz), 7.90(1H, s), 8.18(1H, s), 11.04(1H,brs)

Mass (APCI): 406(M+H)+

EXAMPLE 29

A solution of 10% HCl-MeOH solution (0.5 ml) was added to a mixture of(2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(180 mg) in MeOH (5 ml) and stirred at 15-25° C. for 2 hours. Thereaction mixture was evaporated in vacuo and the residue was trituratedwith small amount MeOH and acetone and the precipitate was collected byfiltration to give(2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-hydroxyacrylamidedihydrochloride (120 mg)

¹H-NMR(DMSO-d6): δ 1.90-2.30 (4H, m), 2.85-3.45 (4H, m), 4.32 (2H, s),6.38 and 6.46 (1H, s), 7.08 (1H, d, J=18.8 Hz), 7.47 (5H, s), 7.58-7.72(2H, m), 8.04 (1H, d, J=18.8 Hz), 8.13 (1H, s), 9.33 (1H, br.s), 11.2(2H, br.s).

The following compounds were obtained according to a similar manner tothat of Example 29.

EXAMPLE 30

4-({5-[(1E)-3-(Hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-N-phenyl-1-piperidinecarboxamidehydrochloride

NMR (DMSO-d6, δ): 1.39-1.55 (2H, m), 1.96-2.02 (2H, m), 2.93-3.05 (2H,m), 4.19-4.29 (3H, m), 6.43 (1H, d, J=15.82 Hz), 6.89-6.97 (1H, m),7.15-7.27 (3H, m), 7.42-7.50 (3H, m), 8.08 (1H, d, J=9.56 Hz), 8.28 (1H,s), 8.63 (1H, s), 9.40 (1H, m)

EXAMPLE 31

(2E)-3-(6-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.91-2.18 (6H, m), 2.95-3.01 (2H, m), 4.33-4.35 (1H,m), 6.41 (1H, d, J=15.86 Hz), 7.08 (1H, d, J=9.38 Hz), 7.44 (1H, d,J=15.86 Hz), 7.54 (2H, d, J=8.42 Hz), 7.71 (2H, d, J=8.42 Hz), 8.03-8.14(2H, m), 11.37 (1H, m)

EXAMPLE 32

(2E)-3-(6-{[(3R)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride (860 mg) was dissolved into water (40 ml), and thesolution was adjusted to ca. pH4.0 by addition of a few drops of aqNaHCO₃ solution. The aqueous solution was chromatographed with HP-20(100 ml), washing with water and eluting with 75% aqueous MeOH. Theelute was concentrated to ca. 10 ml in vacuo, and the resultingprecipitate was collected by filtration.(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide(240 mg) was obtained as colorless powder.

NMR (DMSO-d6, δ): 1.50-1.80 (1H, m), 2.10-2.90 (5H, m), 3.45-3.70 (2H,m), 4.20-4.45 (1H, m), 6.16 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz),7.10-7.40 (7H, m), 7.57 (1H, dd, J=1.5 Hz, J=8.8 Hz), 8.10 (1H, d, J=1.5Hz), 8.91 (1H, br), 10.57 (1H, br)

MASS(API-ES); 339 (M+H)+

EXAMPLE 33

To a suspension of(2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(270 mg) was suspended in methanol (1 mL) and to this suspension wasadded hydrogen chloride in methanol solution (10%, 3 mL). The mixturewas stirred at ambient temperature for 15 minutes and concentrated invacuo. The residual solid was triturated with acetonitrile to give(2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride (228 mg) as a pale tan solid.

NMR (DMSO-d6, δ): 1.29 (9H, s), 1.96-2.67 (2H, m), 3.12-4.02 (2H, m),4.34-4.54 (4H, m), 4.54-4.84 (1H, m), 6.33-6.45 (1H, m), 6.90-7.21 (1H,m), 7.36-7.51 (3H, m), 7.54-7.63 (2H, m), 7.89-8.09 (1H, m), 8.18 (1H,s)

MS (ES+) m/z 395.32(free, M+1)

EXAMPLE 34

10% Metallic hydrogen chloride (1.4 mL) was added to the solution of(2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(0.6 g) in MeOH (12 ml) and the mixture was stirred at ambienttemperature for 3.5 hours. To the reaction mixture was added ethyl etherand isolated precipitate was collected by filtration to give(2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-hydroxyacrylamidehydrochloride (0.42 g)

NMR(DMSO-d6, δ): 1.89-2.33(2H, m), 3.31-3.71(3H, m), 3.72-3.87(1H, m),4.30-4.49(1H, m), 4.63 and 4.50(total 1H, each d, J=15.3 Hz), 7.06 and7.11(total 1H, each s), 7.18 and 7.22(total 1H, each d, J=15.3 Hz),7.45-7.66(4H, m), 8.91(1H, br s)

(+)ESI-MS: 393(M+H)+

The following compounds were obtained according to a similar manner tothat of Example 34.

EXAMPLE 35

(2E)-3-{2-[(1-Benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl}-N-hydroxyacrylamidedihydrochloride

¹H-NMR(DMSO-d6): δ 1.30-1.84 (4H, m), 2.89-3.46 (4H, m), 3.82-4.15 (1H,m), 4.30 (2H, s), 6.52 (1H, d, J=15.4 Hz), 7.09 (1H, s), 7.21 (1H, d,J=15.4 Hz), 7.39-7.51 (3H, m), 7.59-7.72 (2H, m), 8.99 (1H, br.s), 11.21(1H, s),

(+)ESI-MS: 359 (M+1).

EXAMPLE 36

(2E)-3-(2-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)-N-hydroxyacrylamidehydrochloride

NMR(DMSO-d6, δ): 1.37-1.66(2H, m), 1.87-2.15(2H, m), 3.04-3.30(2H, m),3.48-3.75(1H, m), 3.93-4.14(1H, m), 4.17-4.43(1H, m), 6.51(1H, d, J=15.5Hz), 7.13(1H, s), 7.23(1H, d, J=15.5 Hz), 7.43(2H, d, J=8.5 Hz),7.53(2H, d, J=8.5 Hz), 9.16(1H, br s)

(+)ESI-MS: 407(M+H)+

EXAMPLE 37

To a stirred solution of tert-butyl[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate(94 mg) in methanol (2 mL) was added hydrogen chloride methanol reagent10 (0.5 mL, Tokyo Kasei), and the mixture was stirred at ambienttemperature for 30 minutes. The solvent was evaporated to dryness andthe residue was dissolved in the mixture of dioxane (3 ml) and methanol(1 ml). To this solution was added 4N-hydrogen chloride in dioxane (3ml) and the mixture was stirred at ambient temperature for 3 hours. Thesolvent was evaporated to dryness and the residue was triturated withacetonitrile to give(2E)-3-(6-{[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride (63 mg) as a pale yellow powder.

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.42 (3×3H, s), 2.02-2.30 (2H, m),2.42-2.61 (2H, m), 2.64 (1H, dd, J=9.5, 7 Hz), 2.78 (1H, dd, J=9.5, 8Hz), 4.17 (1H, s), 4.29 (2H, q, J=7 Hz), 4.91 (1H, m), 6.49 (1H, d, J=16Hz), 7.08-7.38 (11H, m), 7.69 (1H, d, J=16 Hz), 7.83 (1H, dd, J=8.5, 2Hz), 8.57 (1H, d, J=2 Hz)

MS (ES+) m/z 528.

EXAMPLE 38

To a solution of(2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(168 mg) in EtOH (2 ml) was treated with 10% HCl in MeOH (1.76 ml) andwas stirred at 25° C. for 1 hour. The precipitate was collected, washedwith EtOH, dried under reduced pressure to give(2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-hydroxyacrylamidedihydrochloride (137 mg).

NMR (DMSO-d6, δ): 1.90-2.30(4H, m), 2.90-3.45(4H, m), 4.05-4.30(1H, m),4.25-4.28(2H, m), 6.37(1H, d, J=16.0 Hz), 6.86(1H, brs), 7.16(1H, d,J=16.0 Hz), 7.44-7.69(5H, m), 8.04(1H, s), 8.19(1H, s)

Mass (ESI): 387(M+H)+

The following compounds were obtained according to a similar manner tothat of Example 38.

EXAMPLE 39

(2E)-3-(5-Chloro-6-{[1-(4-fluorobenzyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.90-2.30(4H, m), 2.90-3.45(4H, m), 4.05-4.30(1H, m),4.25-4.28(2H, m), 6.37(1H, d, J=16.0 Hz), 6.86(1H, brs), 7.26-7.45(3H,m), 7.71-7.78(2H, m), 7.95(1H, s), 8.19(1H, s)

Mass (ESI): 405(M+H)+

EXAMPLE 40

(2E)-3-{6-[[1-(4-Chlorobenzoyl)-4-piperidyl](methyl)amino]-3-pyridyl}-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 1.50-2.00(4H, m), 2.80-3.30(2H, m), 3.07(3H, s),4.50-4.80(1H, brs), 6.46(1H, d, J=16.0 Hz), 7.25-7.60(6H, m), 8.09(1H,d, J=8.8 Hz), 8.23(1H, s).

Mass (ESI): 415(M+H)+

EXAMPLE 41

To a solution of(2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(470 mg) in EtOH (2 ml) was treated with 2N HCl in EtOH (2.42 ml) andwas stirred at 25° C. for 1 hour. The precipitate was collected, washedwith EtOH, dried under reduced pressure to give(2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride (308 mg).

NMR (DMSO-d6, δ): 1.90-2.20(4H, m), 2.34(3H, s), 2.90-2.45(4H, m),4.10-4.25(1H, m), 4.20-4.23(2H, m), 6.39(1H, d, J=16.0 Hz), 7.26(1H, d,J=8.8 Hz), 7.35(1H, d, J=16.0 Hz), 7.54(1H, d, J=8.8 Hz), 7.95(1H, s),8.18(1H, s), 11.08(1H, brs)

Mass (ESI): 403(M+H)+

The following compounds were obtained according to a similar manner tothat of Example 41.

EXAMPLE 42

(2E)-3-(5-Chloro-6-{[1-(4-methoxybenzyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.90-2.20(4H, m), 2.90-2.45(4H, m), 3.79(3H, s),4.10-4.25(1H, m), 4.20-4.23(2H, m), 6.38(1H, d, J=16.0 Hz), 7.00(1H, d,J=8.8 Hz), 7.35(1H, d, J=16.0 Hz), 7.58(1H, d, J=8.8 Hz), 7.94(1H, s),8.18(1H, s), 10.98(1H, brs)

Mass (ESI): 417(M+H)+

EXAMPLE 43

(2E)-3-{5-Chloro-6-[(1-isobutyl-4-piperidyl)amino]-3-pyridyl}-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.00(6H, d, J=6.5 Hz), 2.0-2.30(5H, m), 2.80-3.17(4H,m), 3.20-3.30(1H, m), 3.40-3.60(1H, m), 4.10-4.30(1H, m), 6.40(1H, d,J=16.0 Hz), 7.35(1H, d, J=16.0 Hz), 7.95(1H, s), 8.20(1H, s), 10.26(1H,brs)

Mass (ESI): 353(M+H)+

EXAMPLE 44(2E)-3-(5-Chloro-6-{[1-(cyclopropylmethyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 0.36-0.42(2H, m), 0.59-0.68(2H, m), 1.05-1.30(1H, m),1.90-2.25(4H, m), 2.80-3.20(4H, m), 3.40-3.70(2H, m), 4.10-4.40(1H, m),6.41(1H, d, J=16.0 Hz), 7.36(1H, d, J=16.0 Hz), 7.98(1H, s), 8.20(1H,s), 10.86(1H, brs)

Mass (ESI): 351(M+H)+

EXAMPLE 45

(2E)-3-(5-Chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.16(2H, m), 3.06-3.70(4H, m), 4.42(2H, d, J=5.5Hz), 4.60-5.00(1H, m), 6.40(1H, d, J=16.0 Hz), 7.25-7.39(4H, m),7.68-7.76(2H, m), 7.92(1H, s), 8.21(1H, s)

EXAMPLE 46

(2E)-3-(5-Chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.03-2.30(2H, m), 3.10-3.66(4H, m), 4.35(2H, d, J=5.5Hz), 4.65-5.00(1H, m), 6.39(1H, d, J=16.0 Hz), 7.25(2H, d, J=8.8 Hz),7.34(1H, d, J=16.0 Hz), 7.51(1H, d, J=8.8 Hz), 7.91(1H, s), 8.20(1H, s)

EXAMPLE 47

(2E)-3-(5-Chloro-6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.30(2H, m), 3.07-3.70(4H, m), 3.48(3H, s),4.33(2H, d, J=5.5 Hz), 4.60-5.00(1H, m), 6.40(1H, d, J=16.0 Hz),6.99(2H, d, J=8.8 Hz), 7.15-7.40(1H, m), 7.34(1H, d, J=16.0 Hz),7.53-7.89(2H, m), 7.92(1H, s), 8.21(1H, s)

EXAMPLE 48

To[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate(275 mg) was added 4N HCl in dioxane (1.4 mL) and stirred for 15 minutesat ambient temperature. To the reaction mixture was added MeOH (5 mL)and stirred for 15 minutes. The solvent was removed in vacuo and theresidue was suspended in 4N HCl in dioxane (1.24 mL) and stirred for 0.5hour. To the reaction mixture was added CH₃CN and the solvent wasremoved in vacuo. Obtained colorless solid was triturated with CH₃CN togive(2E)-N-hydroxy-3-(6-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidedihydrochloride (211 mg) as colorless powder.

NMR (DMSO-d6, δ): 2.13 (1H, br), 2.34 (0.5H, br), 2.59 (0.5H, br),3.22-3.83 (4H, br), 3.79 (3H, s), 4.41 (1H, m), 4.51 (1H, d), 4.61(0.5H, br), 4.75 (0.5H, br), 6.39 (0.5H, d, J=16.1 Hz), 6.40 (0.5H, d,J=16.1 Hz), 6.99 (1.5H, m), 7.19 (1.5H, m), 7.33 (2H, m), 7.43 (0.5H, d,J=16.1 Hz), 7.44 (0.5H, d, J=16.1 Hz), 8.01 (1H, m), 8.18 (1H, s)

MS (ES+) m/z 369 (M+1)

The following compounds were obtained according to a similar manner tothat of Example 48.

EXAMPLE 49

(2E)-N-Hydroxy-3-[6-({(3R)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylamidedihydrochloride

NMR (DMSO-d6, δ): 0.97-2.62 (2H, m), 3.30-4.10 (5H, m), 4.55-4.73 (2H,m), 6.35 (1H, d, J=16 Hz), 6.88-7.01 (1H, m), 7.41 (1H, d, J=16 Hz),7.48-7.57 (3H, m), 7.89-8.03 (4H, m), 8.16-8.23 (1H, m)

MS (ES+) m/z 422 (M+1)

EXAMPLE 50

(2E)-3-(6-{[(3R)-1-(4-Benzoylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.02-4.73 (9H, m), 6.32 (1H, d, J=16 Hz), 7.40 (1H, d,J=16 Hz), 7.55-7.82 (11H, m), 8.18-8.21 (1H, m)

MS (ES+) m/z 443 (M+1).

EXAMPLE 51

(2E)-3-(6-{[(3R)-1-(2,3-Dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.95-2.41 (2H, m), 3.19 (2H, t, J=9 Hz), 3.24-4.69(7H, m), 4.56 (2H, t, J=9 Hz), 6.29-6.39 (1H, m), 6.79-7.09 (2H, m),7.29-7.50 (3H, m), 7.87-7.99 (1H, m), 8.17-8.21 (1H, s)

MS (ES+) m/z 381 (M+1)

EXAMPLE 52

(2E)-3-(6-{[(3R)-1-(1-Benzofuran-2-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide

NMR (DMSO-d6, δ): 1.61-4.44 (9H, m), 6.17 (1H, d, J=16 Hz), 6.52 (1H, d,J=8 Hz), 7.19-7.36 (4H, m), 7.52-7.64 (3H, m), 8.10-8.15 (1H, m)

MS (ES+) m/z 379 (M+1)

EXAMPLE 53

(2E)-3-(6-{[(3R)-1-(1-Benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide

NMR (DMSO-d6, δ): 1.72-4.53 (9H, m), 6.20 (1H, d, J=16 Hz), 6.54 (1H, d,J=8 Hz), 6.95-8.16 (8H, m)

MS (ES+) m/z 379 (M+1)

EXAMPLE 54

(2E)-N-Hydroxy-3-(6-{[(3R)-1-(3-phenylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.00 (2H, m), 2.06 (1H, br), 2.30 (0.5H, br), 2.54(0.5H, br), 2.66 (2H, t, J=8.0 Hz), 3.12-4.01 (6H; br), 4.58 (1H, br),4.69 (1H, br), 6.38 (1H, d, J=16.1 Hz), 6.96 (0.5H, d, J=8.0 Hz), 7.04(0.5H, d, J=9.2 Hz), 7.23 (3H, m), 7.31 (2H, m), 7.43 (1H, d, J=16.1Hz), 7.99 (1H, m), 8.21 (1H, s)

MS (ES+) m/z 367 (M+1)

EXAMPLE 55

(2E)-3-[6-({(3R)-1-[4-(Dimethylamino)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]-N-hydroxyacrylamidetrihydrochloride

NMR (DMSO-d6, δ): 2.12 (1H, br), 2.37 (1H, br), 2.96 (6H, s), 3.18-4.00(4H, br), 4.30 (1H, br), 4.40 (1H, d, J=5.5 Hz), 4.58 (0.5H, br), 4.72(0.5H, br), 6.39 (0.5H, d, J=16.1 Hz), 6.40 (0.5H, d, J=16.1 Hz), 6.92(2H, br), 7.01 (0.5H, d, J=8.1 Hz), 7.15 (0.5H, d, J=8.1 Hz), 7.43 (1H,m), 7.48 (2H, m), 8.03 (1H, m), 8.20 (1H, s)

MS (ES+) m/z 382 (M+1)

EXAMPLE 56

(2E)-N-Hydroxy-3-(6-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.11 (1H, br), 2.39 (1H, br), 3.11-3.71 (4H, br), 3.82(1.5H, s), 3.87 (1.5H, s), 4.39 (1H, br), 4.45 (1H, br), 4.59 (0.5H,br), 4.71 (0.5H, br), 6.36 (1H, d, J=16.1 Hz), 6.93 (1H, m), 7.02 (1H,m), 7.12 (1H, dd, J=8.4, 4.5 Hz), 7.43 (2H, m), 7.57 (1H, m), 7.96 (1H,m), 8.18 (1H, s)

MS (ES+) m/z 369 (M+1)

EXAMPLE 57

To a solution of tert-butyl[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate[(251 g) in MeOH (37 mL) was added hydrogen chloride methanol reagent 10(9.28 mL, Tokyo Kasei), and the mixture was stirred at ambienttemperature for 1 hour. The solvent was removed in vacuo and the residuewas dissolved in dioxane (12 mL). To the reaction mixture was added 4NHCl in dioxane and stirred for 1 hour at ambient temperature. To thereaction mixture was added CH₃CN and the solvent was removed in vacuo.Obtained colorless solid was triturated with CH₃CN to give(2E)-3-(6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride (1.87 g) as colorless powder.

NMR (CDCl₃, δ): 2.08 (1H, m), 2.34 (1H, m), 3.23-3.81 (4H, m), 4.45 (1H,m), 4.54 (1H, d, J=5.5 Hz), 4.58 (0.5H, br), 4.69 (0.5H, br), 6.35(0.5H, d, J=16.1 Hz), 3.36 (0.5H, d, J=16.1 Hz), 6.90 (0.5H, br), 7.03(0.5H, br), 7.30 (1H, m), 7.41 (1H, m), 7.48-7.60 (3H, m), 7.95 (1H, m),8.18 (1H, s),

MS (ES+) m/z 357 (M+1)

The following compounds were obtained according to a similar manner tothat of Example 57.

EXAMPLE 58

(2E)-N-Hydroxy-3-[6-({(3R)-1-[4-(trifluoromethyl)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.98-2.76 (2H, m), 3.17-4.25 (4H, m), 4.50-4.79 (3H,m), 6.29-6.45 (1H, m), 6.87-7.18 (1H, m), 7.36-7.48 (1H, m), 7.81-8.08(5H, m), 8.19 (1H, brs)

MS (ES+) m/z 407.33(free, M+1)

EXAMPLE 59

(2E)-N-Hydroxy-3-[6-({(3R)-1-[4-(trifluoromethoxy)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.92-2.80 (2H, m), 3.14-4.23 (4H, m), 0.43-4.78 (3H,m), 6.30-6.46 (1H, m), 6.86-7.16 (1H, m), 7.37-7.53 (3H, m), 7.76-7.86(2H, m), 7.88-8.08 (1H, m), 8.19 (1H, s)

MS (ES+) m/z 423.25(free, M+1)

EXAMPLE 60

(2E)-3-(6-{(3R)-1-(Cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 0.77-1.34 (5H, m), 1.52-1.91 (6H, m), 1.97-2.62 (4H,m), 3.00-4.09 (4H, m), 4.51-4.76 (1H, m), 6.36 (1H, d, J=15.8 Hz),6.88-7.10 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.91-8.01 (1H, m), 8.20 (1H,s)

MS (ES+) m/z 345.41(free, M+1)

EXAMPLE 61

(2E)-3-(6-{[(3R)-1-(1-Cyclohexen-1-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.45-1.66 (4H, m), 1.90-2.20 (5H, m), 2.30-2.63 (1H,m), 2.99-3.90 (6H, m), 4.52-4.81 (1H, m), 5.94-6.04 (1H, m), 6.38 (1H,d, J=15.8 Hz), 6.93-7.17 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.91-8.09(1H, m), 8.21 (1H, brs)

MS (ES+) m/z 343.50(free, M+1)

EXAMPLE 62

(2E)-3-(6-{[(3R)-1-(2-Fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.12 (1H, br), 2.37 (1H, br), 2.60 (1H, br), 3.25 (1H,br), 3.45 (1H, br), 3.66 (1H, br), 3.91 (1H, br), 4.50 (1H, br), 4.56(1H, d, J=5.1 Hz), 4.59 (0.5H, br), 4.70 (0.5H, br), 6.35 (1H, d, J=16.1Hz), 6.91 (0.5H, br), 6.98 (0.5H, br), 7.30 (1H, d, J=7.3 Hz), 7.35 (1H,d, J=9.1 Hz), 7.41 (1H, d, J=16.1 Hz), 7.52 (1H, m), 7.78 (1H, m), 7.94(1H, m), 8.19 (1H, s)

MS (ES+) m/z 357 (M+1)

EXAMPLE 63

(2E)-N-Hydroxy-3-(6-{[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidetrihydrochloride

NMR (DMSO-d6, δ): 2.21 (1H, br), 2.51 (1H, br), 3.61 (2H, br), 3.76 (1H,br), 3.95 (1H, br), 4.72 (1H, br), 4.93 (2H, s), 6.38 (1H, d, J=15.8Hz), 7.08 (1H, d, J=9.5 Hz), 7.43 (1H, d, J=15.8 Hz), 7.69 (1H, m), 7.71(1H, d, J=8.4 Hz), 7.84 (1H, m), 8.04 (2H, m), 8.20 (1H, s), 8.50 (1H,d, J=8.1 Hz)

MS (ES+) m/z 390 (M+1)

EXAMPLE 64

(2E)-N-Hydroxy-3-(6-{[(3R)-1-(3-quinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamidetrihydrochloride

NMR (DMSO-d6, δ): 2.10 (1H, br), 2.63 (1H, br), 3.35 (1H, br), 3.49 (1H,br), 3.69 (1H, br), 3.90 (1H, br), 4.58 (1H, br), 4.72 (1H, br), 4.80(1H, br), 6.35 (1H, d, J=16.1 Hz), 6.91 (0.5H, br), 7.03 (0.5H, br),7.41 (1H, d, J=16.1 Hz), 7.76 (1H, t, J=7.7 Hz), 7.93 (2H, m), 8.08 (1H,d, J=7.7 Hz), 8.14 (1H, d, J=8.1 Hz), 8.19 (1H, s), 8.79 (1H, d, J=6.6Hz), 9.23 (1H, d, J=8.1 Hz)

MS (ES+) m/z 390 (M+1)

EXAMPLE 65

(2E)-N-Hydroxy-3-[6-({(3R)-1-[(5-methyl-2-thienyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.07 (1H, br), 2.31 (1H, br), 2.45 (3H, s), 3.23 (1H,br), 3.37 (1H, br), 3.52 (1H, br), 3.81 (1H, br), 4.56 (1H, d, J=4.4Hz), 4.57 (0.5H, br), 4.64 (1H, d, J=5.1 Hz), 4.67 (0.5H, br), 6.35 (1H,d, J=16.1 Hz), 6.80 (1H, br), 6.90 (0.5H, br), 6.98 (0.5H, br), 7.19(1H, m), 7.42 (1H, d, J=16.1 Hz), 7.93 (1H, m), 8.19 (1H, s)

MS (ES+) m/z 359 (M+1)

EXAMPLE 66

(2E)-N-Hydroxy-3-[6-({(3R)-1-[(5-methyl-2-furyl)methyl]-3-pyrrolidinyl}amino-3-pyridyl]acrylamidedihydrochloride

NMR (DMSO-d6, δ): 2.09 (2H, br.), 2.26 (1.5H, s), 2.29 (1.5H, s), 3.26(1H, br.), 3.53 (2H, br.), 3.86 (1H, br.), 4.44 (1H, s), 4.53 (1H, s),4.64 (1H, br.d), 6.15 (1H, m), 6.39 (1H, d, J=15.8 Hz), 6.60 (1H, s),7.04 (1H, m), 7.43 (1H, d, J=15.4 Hz), 8.00 (1H, br.), 8.20 (1H, s)

MS (ES+) m/z 343 (M+1)

EXAMPLE 67

(2E)-3-{6-[((3R)-1-{(2E)-3-[4-(Dimethylamino)phenyl]-2-propen-1-yl}-3-pyrrolidinyl)amino]-3-pyridyl}-N-hydroxyacrylamidetrihydrochloride

NMR (DMSO-d6, δ): 2.23 (2H, br.), 3.00 (6H, s), 3.07 (1H, br.), 3.43(2H, br.), 3.71 (1H, br.), 3.97 (1H, br.), 4.07 (1H, br.), 4.65 (0.5H,br.), 4.77 (0.5H, br.), 6.27 (1H, br.), 6.42 (1H, d, J=15.8 Hz), 6.80(1H, d, J=15.4 Hz), 7.09 (2H, br.), 7.22 (1H, d, J=8.4 Hz), 7.44 (3H,m), 8.07 (1H, m), 8.19 (1H, s)

MS (ES+) m/z 408 (M+1)

EXAMPLE 68

(2E)-3-(6-{[(3R)-1-(2,2-Dimethylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidedihydrochloride

NMR (DMSO-d6, δ): 1.06 (4.5H, s), 1.07 (4.5H, s), 2.08 (1H, m), 2.45(1H, m), 3.16 (1H, m), 3.25 (1H, m), 3.39-3.92 (4H, br), 4.12 (1H, m),4.59 (0.5H, br), 4.71 (0.5H, br), 6.35 (1H, d, J=16.1 Hz), 6.94 (1H,br.d), 7.42 (1H, d, J=16.1 Hz), 7.94 (1H, br.d), 8.21 (1H, br)

MS (ES+) m/z 319 (M+1)

EXAMPLE 69

To a solution of(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (76 mg) in MeOH (1.3 mL) was added hydrogen chloride methanolreagent 10 (0.32 mL, Tokyo Kasei), and the mixture was stirred atambient temperature for 1 hour. To the reaction mixture was added CH₃CNand the solvent was removed in vacuo. Obtained colorless solid wastriturated with CH₃CN to give(2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamidehydrochloride (64.1 mg) as colorless powder.

NMR (DMSO-d6, δ): 1.89 (1H, m), 2.18 (1H, m), 3.24 (0.5H, m), 3.45(0.5H, m), 3.59 (1H, m), 3.67 (1H, m), 3.78 (1H, m), 4.03 (0.5H, m),4.12 (0.5H, m), 6.15 (0.5H, d, J=15.8 Hz), 6.20 (0.5H, d, J=15.8 Hz),6.59 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.8 Hz), 7.26-7.36 (3H, m),7.47-7.59 (5H, m)

EXAMPLE 70

To a solution of(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(1.89 g) in MeOH (32 mL) was added hydrogen chloride methanol reagent 10(8.0 mL, Tokyo Kasei), and the mixture was stirred at ambienttemperature for 0.5 hour. The reaction mixture was diluted with AcOEtand the precipitate was collected with filtration to give(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride (1.18 g) as colorless powder.

NMR (DMSO-d6, δ): 2.02 (1H, br), 2.25 (1H, br), 3.34-3.64 (4H, br), 3.85(1H, m), 4.40 (0.5H, br), 4.50 (0.5H, br), 6.35 (0.5H, d, J=16.1 Hz),6.37 (0.5H, d, J=16.1 Hz), 6.98 (0.5H, m), 7.06 (0.5H, m), 7.38-7.60(5H, m), 8.01 (1H, m), 8.14 (0.5H, s), 8.23 (0.5H, s)

MS (ES+) m/z 387 (M+1)

The following compounds were obtained according to a similar manner tothat of Example 70.

EXAMPLE 71

(2E)-3-(6-{[(3S)-1-(4-Chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamidehydrochloride

NMR (DMSO-d6, δ): 2.02 (1H, br), 2.25 (1H, br), 3.34-3.64 (4H, br), 3.85(1H, m), 4.40 (0.5H, br), 4.50 (0.5H, br), 6.35 (0.5H, d, J=16.1 Hz),6.37 (0.5H, d, J=16.1 Hz), 6.98 (0.5H, m), 7.06 (0.5H, m), 7.38-7.60(5H, m), 8.01 (1H, m), 8.14 (0.5H, s), 8.23 (0.5H, s)

MS (ES+) m/z 387 (M+1)

EXAMPLE 72

To a solution of(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(500 mg) in MeOH (5 mL) was added hydrogen chloride methanol reagent 10(2.38 mL, Tokyo Kasei), and the mixture was stirred at ambienttemperature for 1 hour. To the reaction mixture was added CH₃CN and thesolvent was removed in vacuo. Obtained colorless solid was trituratedwith CH₃CN to give(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamidehydrochloride (257.4 mg) as colorless powder.

NMR (DMSO-d6, δ): 1.94 (1H, m), 2.01 (0.5H, m), 2.29 (0.5H, m), 3.00(0.5H, m), 3.19 (1.5H, m), 3.29-3.53 (2.5H, m), 3.73 (0.5H, m), 4.18(0.5H, m), 4.31 (0.5H, m), 4.40 (1H, d, J=5.9 Hz), 4.44 (1H, d, J=5.9Hz), 6.20 (1H, d, J=16.1 Hz), 6.61 (1H, d, J=8.8 Hz), 6.63 (1H, d, J=8.8Hz), 7.33 (2H, m), 7.44 (3H, m), 7.64 (2H, m)

MS (ES+) m/z 338 (M+1)

EXAMPLE 73

To a solution of(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(306 mg) in MeOH (5.6 mL) was added hydrogen chloride methanol reagent10 (1.4 mL, Tokyo Kasei), and the mixture was stirred at ambienttemperature for 2 hours. To the reaction mixture was added Men and thesolvent was removed in vacuo. Obtained colorless solid was trituratedwith Men to give(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-hydroxyacrylamidedihydrochloride (202.1 mg) as colorless powder.

NMR (DMSO-d6, δ): 2.16 (1H, m), 2.28 (3H, s), 2.65 (1H, m), 3.22 (1H,m), 3.48 (2H, m), 3.58 (1H, m), 4.44 (1H, d, J=5.8 Hz)”, 4.49 (1H, d,J=5.8 Hz), 4.98 (1H, br), 6.39 (1H, d, J=16.1 Hz), 7.41 (1H, d, J=16.1Hz), 7.45 (3H, m), 7.63 (2H, m), 7.88 (1H, be), 8.09 (1H, s)

MS (ES+) m/z 353 (M+1)

EXAMPLE 74

To a solution of(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(1.43 g) in methanol (16 mL) was added hydrogen chloride in methanol(6.24 mL). After stirring at room temperature for 1 hour, the reactionmixture was evaporated in vacuo and triturated with ethyl acetate togive(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride (1.40 g).

¹H-NMR (300 MHz, DMSO-d6) d 1.93-2.38 (2H, m), 3.00-3.79 (4H, m),4.37-4.63 (3H, m), 6.63 (1H, d, J=15 Hz), 7.39 (1H, d, J=15 Hz), 7.52(2H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz), 8.00-8.16 (2H, m)

MS (ES+) m/z 374 (M+1)

The following compounds were obtained in a similar manner to that ofExample 74.

EXAMPLE 75

(2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.81-1.03 (2H, m), 1.04-1.35 (3H, m),1.35-2.20 (10H, m), 2.56-2.76 (1H, m), 2.76-3.13 (3H, m), 3.16-3.65 (2H,m), 4.03-4.75 (1H, m), 6.63 (1H, d, J=15.0 Hz), 7.40 (1H, d, J=15.0 Hz),7.76-7.89 (0.6H, m), 8.03 (1H, s), 8.05-8.35 (0.4H, m), 8.15 (1H, s),9.80-10.02 (1H, br.s)

MS (ES+) m/z 360(M+1, free)

EXAMPLE 76

(2E)-3-(5-{[(3R)-1-Benzyl-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.31-1.53 (1H, m), 1.74-2.16 (3H, m),2.56-2.78 (1H, m), 2.78-3.05 (1H, m), 3.23-3.40 (1H, m), 3.40-3.54 (1H,m), 4.20-4.45 (3H, m), 6.61 (1H, d, J=15 Hz), 7.36 (1H, d, J=15 Hz),7.42-7.54 (3H, m), 7.54-7.70 (2H, m), 7.70-7.94 (1H, m), 8.00 (1H, s),8.10 (1H, s)

MS (ES+) m/z 354

EXAMPLE 77

(2E)-3-(5-{[(3R)-1-Cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, CD₃OD)d 1.10-1.30 (1H, m), 1.30-1.77 (6H, m), 1.85-2.06(3H, m), 2.06-2.30 (3H, m), 2.85 (1H, t, J=11 Hz), 2.99-3.15 (1H, m),3.15-3.33 (2H, m), 3.45-3.58 (1H, m), 3.67-3.86 (1H, m), 4.28-4.44 (1H,m), 6.76 (1H, d, 3=15 Hz), 7.53 (1H, d, J=15 Hz), 8.11-8.24 (2H, m)

MS (ES+) m/z 346

EXAMPLE 78

(2E)-N-Hydroxy-3-(5-{[(3R)-1-(4-methylbenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.30-1.52 (1H, m), 1.70-2.15 (4H, m), 2.33(3H, s), 2.54-2.71 (1H, m), 2.71-2.99 (1H, m), 3.21-3.36 (1H, m),3.36-3.50 (1H, m), 4.23-4.44 (2H, m), 6.61 (1H, d, J=15 Hz), 7.10 (1H,s), 7.25 (2H, d, J=8 Hz), 7.30 (1H, s), 7.36 (1H, d, J=15 Hz), 7.41-7.55(3H, m), 7.80 (1H, br peak), 7.93-8.06 (1H, m), 8.10 (1H, s)

MS (ES+) m/z 368

EXAMPLE 79

(2E)-3-(5-{[(3R)-1-(4-Chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.34-1.56 (1H, m), 1.70-2.11 (4H, m),2.56-2.75 (1H, m), 2.75-2.93 (1H, m), 3.20-3.38 (1H, m), 3.38-3.55 (1H,m), 4.22-4.45 (2H, m), 6.62 (1H, d, J=15 Hz), 7.40 (1H, d, J=15 Hz),7.49-7.58 (2H, m), 7.58-7.70 (2H, m), 7.70-7.82 (1H, m), 7.95-8.06 (1H,m), 8.11 (1H, s)

MS (ES+) m/z 388

EXAMPLE 80

(2E)-3-(5-{[(3R)-1-Cyclopentyl-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.39-1.52 (3H, m), 1.52-2.04 (9H, m),2.56-2.78 (1H, m), 2.78-3.10 (1H, m), 3.20-4.50 (4H, m), 6.63 (1H, d,J=15 Hz), 7.13 (1H, s), 7.30 (1H, s), 7.39 (1H, d, J=15 Hz), 7.47 (1H,s), 7.85 (1H, br peak), 7.98-8.10 (1H, m), 8.10-8.21 (1H, m)

MS (ES+) m/z 332

EXAMPLE 81

(2E)-3-(5-{[(3R)-1-(Cyclopentylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.16-1.35 (2H, m), 1.35-1.69 (4H, m),1.69-2.07 (5H, m), 2.18-2.36 (1H, m), 2.56-2.75 (1H, m), 2.75-2.96 (1H,m), 2.96-3.19 (2H, m), 3.19-4.20 (3H, m), 4.20-4.42 (1H, m), 6.63 (1H,d, J=15 Hz), 7.11 (1H, s), 7.28 (1H, s), 7.40 (1H, d, J=15 Hz), 7.45(1H, s), 7.76-7.91 (1H, m), 8.01-8.11 (1H, m), 8.15 (1H, s)

MS (ES+) m/z 346

EXAMPLE 82

(2E)-3-(5-{[(R)-1-Benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-Nhydroxyacrylamide dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.95-2.36 (2H, m), 2.99-3.78 (4H, m),4.33-4.62 (3H, m), 6.62 (1H, dd, J=2, 15 Hz), 7.38 (1H, d, J=15 Hz),7.43-7.47 (3H, m), 7.59-7.65 (2H, m), 8.00-8.15 (2H, m)

MS (ES+) m/z 340 (M+1)

EXAMPLE 83

(2E)-N-Hydroxy-3-(5-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.95-2.38 (2H, m), 2.32 (3H, s), 2.98-3.78(4H, m), 4.31-4.61 (3H, m), 6.63 (1H, dd, J=2, 15 Hz), 7.22-7.28 (2H,m), 7.39 (1H, d, J=15 Hz), 7.46-7.52 (2H, m), 8.00-8.15 (2H, m)

MS (ES+) m/z 354 (M+1)

EXAMPLE 84

(2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.85-1.03 (2H, m), 1.04-1.32 (3H, m),1.54-1.77 (4H, m), 1.78-1.90 (2H, m), 2.04 (1H, m), 2.33 (1H, m),2.92-3.85 (6H, m), 4.55 (1H, m), 6.63 (1H, d, J=15.3 Hz), 7.40 (1H, d,J=15.3 Hz), 8.05 (1H, d, J=8.4 Hz), 8.11-8.32 (3H, m), 10.44 (1H, br-s)

MS (ES+) m/z 346

EXAMPLE 85

To a stirred solution of(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide(300 mg) in 95% ethanol (3 mL) was added 4-methylbenzenesulfonic acidhydrate (168 mg) at ambient temperature. After stirring at the sametemperature for one hour, additional 95% ethanol (1.5 mL) was added tothe mixture. The precipitate was collected after two hours to afford(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide4-methylbenzenesulfonate (253 mg) as a pale brown solid.

¹H-NMR (300 MHz, CD₃OD) δ 2.07-2.26 (1H, m), 2.36 (3H, s), 2.43-2.65(1H, m), 3.24-3.49 (2H, m), 3.54-3.82 (2H, m), 4.38 (1H, d, J=12.8 Hz),4.46 (1H, d, J=12.8 Hz), 4.51-4.65 (1H, m), 6.68 (1H, d, J=15.4 Hz),7.22 (2H, d, J=8.1 Hz), 7.41-7.57 (6H, m), 7.70 (2H, d, J=8.1 Hz), 7.98(1H, s), 8.05 (1H, s)

EXAMPLE 86

To a solution of(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride (1.00 g) in water (10 mL) was added saturated NaHCO₃ at4° C. (to pH 7-8). The mixture was extracted with CHCl₃ three times. Theconbined organic layer was dried over Na₂SO₄, filtered, and evaporatedin vacuo to give(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide(796 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 1.58-1.72 (1H, m), 2.16-2.29 (1H, m),2.36-2.48 (2H, m), 2.61-2.80 (2H, m), 3.58 (2H, s), 4.24-4.36 (1H, m),6.56 (1H, d, J=15 Hz), 7.20-7.38 (6H, m), 7.73 (1H, d, J=7 Hz), 7.97(1H, s), 8.07 (1H, s), 8.97 (1H, brs), 10.70 (1H, brs)

MS (ES+) m/z 340 (M+1)

The following compound was obtained in similar manners to those ofExamples 74 and 86.

EXAMPLE 87

(2E)-N-Hydroxy-3-(5-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]-amino}-2-pyrazinyl)acrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.55-1.72 (1H, m), 2.12-2.29 (1H, m), 2.27(3H, s), 2.32-2.49 (2H, m), 2.57-2.78 (2H, m), 3.51 (1H, d, J=13.2 Hz),3.55 (1H, d, J=13.2 Hz), 4.21-4.36 (1H, m), 6.56 (1H, d, J=15.0 Hz),7.11 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz), 7.33 (1H, d, J=15.0 Hz),7.71 (1H, d, J=6.2 Hz), 7.96 (1H, s), 8.06 (1H, s)

EXAMPLE 88

To a solution of(2E)-3-(5-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(46 mg) in ethanol (1 mL) was added 2N hydrogen chloride in ethanol(0.26 mL). After stirring at room temperature for 2 hours, the reactionmixture was evaporated in vacuo and triturated with ethyl acetate togive(2E)-3-(5-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride (31 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 1.94-2.39 (8H, m), 3.04-4.69 (7H, m), 6.63(1H, dd, J 2, 16 Hz), 7.12-7.27 (2H, m), 7.36-7.46 (2H, m), 8.01-8.24(2H, m).

MS (ES+) m/z 368 (M+1).

EXAMPLE 89

To a mixture of(2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(288 mg) and ethanol (2.9 mL) was added 2N hydrogen chloride in ethanol(1.53 mL). After stirring at room temperature for 2 hours, resultingprecipitate was collected by filtration, and washed with ethanol to give(2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidehydrochloride (138 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 1.86-2.29 (2H, m), 3.26-3.84 (4H, m),4.32-4.51 (1H, m), 6.56-6.66 (1H, m), 7.31-7.61 (5H, m), 7.98-8.17 (2H,m).

MS (ES+) m/z 388 (M+1).

The following compounds were obtained in a similar manner to that ofExample 89.

EXAMPLE 90

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.94-2.45 (2H, m), 3.10-4.66 (7H, m), 6.63(1H, d, J=16 Hz), 7.40 (1H, d, J=16 Hz), 7.45-7.63 (3H, m), 7.85-8.18(4H, m), 11.1 (1H, brs).

MS (ES+) m/z 374 (M+1).

EXAMPLE 91

(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.94-2.36 (2H, m), 3.01-3.80 (4H, m),4.39-4.62 (3H, m), 6.63 (1H, d, J=16 Hz), 7.39 (1H, d, J=16 Hz),7.44-7.63 (3H, m), 7.77 (1H, s), 8.00-8.29 (3H, m), 11.4 (1H, brs).

MS (ES+) m/z 374 (M+1).

EXAMPLE 92

To a solution of tert-butyl[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl)-2-pyridinyl)carbamate(179 mg, 0.35 mmol) in MeOH (1 mL) was added hydrogen chloride methanolreagent 10 (3 mL, Tokyo Kasei), and the mixture was stirred at ambienttemperature for 1 hr. The solvent was removed in vacuo and the residuewas dissolved in dioxane (1 mL). To the reaction mixture was added 4NHCl in dioxane (4 mL) and stirred for 1 hr at ambient temperature. Tothe reaction mixture was added MeCN and the solvent was removed invacuo. Obtained colorless solid was triturated with MeCN to give(2E)-3-(6-{[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride (115 mg, 85%) as colorless powder.

¹H-NMR (300 MHz, DMSO-d6) δ 1.16-1.40 (2H, m), 1.40-1.72 (4H, m),1.72-1.93 (2H, m), 1.93-2.53 (3H, m), 3.07-3.36 (3H, m), 3.36-4.09 (3H,m), 4.52-4.75 (1H, m), 6.36 (1H, d, J=15.7 Hz), 6.88-7.08 (1H, m), 7.43(1H, d, J=15.8 Hz), 7.91-8.01 (1H, m), 8.12 (1H, s);

The following compounds were obtained in a similar manner to that ofExample 92.

EXAMPLE 93

(2E)-3-(6-{[(3R)-1-(cycloheptylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.15-1.34 (2H, m), 1.34-1.71 (7H, m),1.71-1.99 (3H, m), 1.99-2.19 (1H, m), 2.25-2.65 (1H, m), 3.02-3.24 (3H,m), 3.24-3.92 (3H, m), 3.92-4.11 (1H, m), 4.53-7.76 (1H, m), 6.36 (1H,d, J=15.8 Hz), 6.87-7.06 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.92-8.03(1H, m), 8.20 (1H, s), 10.27 (1H, br peak); MS (ES+) m/z 359.

EXAMPLE 94

(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.85-1.06 (2H, m), 1.06-1.35 (3H, m),1.54-1.78 (4H, m), 1.78-1.95 (2H, m), 1.95-2.18 (1H, m), 2.25-2.65 (1H,m), 2.97-4.09 (6H, m), 4.52-4.76 (1H, m), 6.73-7.00 (2H, m), 7.08 (1H,s), 7.25 (1H, s), 7.42 (1H, s), 7.95 (1H, d, J=8.6 Hz), 8.25 (1H, s);

MS (ES+) m/z 363.

EXAMPLE 95

(2E)-3-(6-{[(3R)-1-(1-adamantylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (16H, m), 1.90-2.03 (3H, m),2.03-2.16 (1H, m), 2.95-4.20 (3H, m), 4.53-4.80 (1H, m), 6.38 (1H, d,J=15.4 Hz), 6.89-7.12 (1H, m), 7.44 (1H, d, J=15.4 Hz), 8.00 (1H, d,J=9.5 Hz), 8.21 (1H, s).

EXAMPLE 96

To the solution of(2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(3.2 g, 7.1 mmol) in EtOH (16 ml) was added 2M ethanlic hydrogenchloride (17.5 mL) and the mixture was stirred at ambient temperaturefor 3 hrs. To the reaction mixture was added IPE and isolatedprecipitate was collected by filtration to give(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride (2.3 g, 74%) as an amorphous powder.

¹H-NMR (300 MHz, DMSO-d6) δ 1.40-1.61 (1H, m), 1.74-2.21 (3H, m),2.60-2.80 (1H, m), 2.80-3.01 (1H, m), 3.01-3.14 (2H, m), 3.21-3.38 (2H,m), 3.38-3.75 (2H, m), 4.23-4.42 (1H, m), 6.64 (1H, d, J=15.2 Hz),7.20-7.48 (6H, m), 7.84 (1H, br peak), 8.00-8.12 (1H, m), 8.12-8.26 (1H,m); MS (ES+) m/z 368.

The following compounds were obtained in a similar manner to that ofExample 96.

EXAMPLE 97

(2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.30-1.66 (1H, m), 1.66-2.17 (3H, m),2.60-4.00 (4H, m), 4.16-4.60 (3H, m), 6.21-6.44 (1H, m), 6.55-7.10 (2H,m), 7.32-7.67 (6H, m), 7.79-8.01 (1H, m), 8.11-8.38 (1H, m); MS (ES+)m/z 353.

EXAMPLE 98

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxy-2-methylacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.80-1.04 (2H, m), 1.04-1.32 (4H, m),1.53-1.75 (5H, m), 1.75-1.90 (2H, m), 1.90-2.20 (4H, m), 2.20-2.65 (1H,m), 3.00-3.20 (3H, m), 3.94-4.10 (1H, m), 4.51-4.73 (1H, m), 6.87-7.04(2H, m), 7.85 (1H, d, J=9.0 Hz), 8.03 (1H, s); MS (ES+) m/z 359.

EXAMPLE 99

(2E)-3-(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.86-1.05 (2H, m), 1.05-1.35 (3H, m),1.35-2.15 (10H, m), 2.65-3.10 (3H, m), 3.20-4.00 (3H, m), 4.30-4.62 (1H,m), 6.37 (1H, d, J=16.1 Hz), 6.90-7.11 (1H, m), 7.35-7.51 (1H, m),7.90-8.10 (1H, m), 8.15-8.30 (1H, m);

EXAMPLE 100

(2E)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.00-1.69 (8H, m), 1.75-2.15 (7H, m),2.58-3.90 (4H, m), 4.25-4.55 (1H, m), 6.26-6.41 (1H, m), 6.80-7.05 (1H,m), 7.35-7.50 (1H, m), 7.85-8.06 (1H, m), 8.21 (1H, s); MS (ES+) m/z345.

EXAMPLE 101

(2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.31-1.66 (1H, m), 1.73-2.19 (3H, m),2.64-3.09 (2H, m), 3.09-4.00 (2H, m), 4.20-4.65 (3H, m), 6.35 (1H, d,J=15.7 Hz), 6.85-7.10 (1H, m), 7.41 (1H, d, J=16.0 Hz), 7.55 (2H, d,J=8.2 Hz), 7.65 (2H, d, J=7.8 Hz), 7.89-8.11 (1H, m), 8.19 (1H, s);

MS (ES+) m/z 387.

EXAMPLE 102

(2E)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.41-1.64 (3H, m), 1.64-2.18 (10H, m),2.72-4.00 (4H, m), 4.21-4.60 (1H, m), 6.30-6.44 (1H, m), 6.94-7.11 (1H,m), 7.36-7.50 (1H, m), 7.94-8.08 (1H, m), 8.15-8.25 (1H, m);

MS (ES+) m/z 331.

EXAMPLE 103

(2E)-N-hydroxy-3-(6-{[(3R)-1-(4-methylbenzyl)-3-piperidinyl]amino}-3-pyridinyl}acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.31-1.65 (1H, m), 1.74-2.16 (4H, m), 2.33(3H, s), 2.65-4.20 (3H, m), 4.20-4.70 (3H, m), 6.40 (1H, d, J=15.9 Hz),6.91-7.16 (1H, m), 7.27 (2H, d, J=7.7 Hz), 7.35-7.59 (3H, m), 7.95-8.12(1H, m), 8.20 (1H, br s).

EXAMPLE 104

(2Z)-2-fluoro-N-hydroxy-3-(6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.90-2.20 (2H, m), 2.20-2.40 (4H, m),2.40-3.86 (3H, m), 4.24-4.76 (3H, m), 6.70-7.10 (2H, m), 7.20-7.30 (2H,m), 7.45-7.55 (2H, m), 7.91-8.06 (1H, m), 8.24 (1H, s);

MS (ES+) m/z 371.

EXAMPLE 105

(2Z)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.93-2.21 (2H, m), 2.21-4.00 (4H, m),4.34-4.80 (3H, m), 6.70-7.15 (2H, m), 7.53 (2H, d, J=8.2 Hz), 7.62-7.75(2H, m), 8.00 (1H, t, J=9.9 Hz), 8.22 (1H, s);

MS (ES+) m/z 391.

EXAMPLE 106

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.96-1.94 (12H, m), 1.94-2.14 (1H, m),2.38-2.67 (1H, m), 2.94-4.15 (6H, m), 6.39 (1H, d, J=16.0 Hz), 6.95-7.20(1H, m), 7.45 (1H, d, J=16.3 Hz), 7.92-8.14 (1H, m), 8.20 (1H, br s);

MS (ES+) m/z 373.

EXAMPLE 107

(2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.37-2.14 (5H, m), 3.04-4.20 (4H, m), 6.41(1H, d, J=15.9 Hz), 6.95-7.95 (7H, m), 7.95-8.38 (1H, m);

MS (ES+) m/z 401.

EXAMPLE 108

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.85-1.07 (2H, m), 1.07-1.36 (3H, m),1.36-2.15 (10H, m), 2.65-3.10 (3H, m), 3.20-4.10 (3H, m), 4.30-4.65 (1H,m), 6.39 (1H, d, J=16.1 Hz), 6.94-7.12 (1H, m), 7.34-7.51 (1H, m),7.91-8.09 (1H, m), 8.15-8.30 (1H, m).

EXAMPLE 109

(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.34-1.54 (1H, m), 1.74-2.15 (4H, m),2.59-3.23 (2H, m), 3.23-3.58 (2H, m), 4.21-4.46 (2H, m), 6.61 (1H, d,J=15.2 Hz), 7.38 (1H, d, J=15.2 Hz), 7.45-7.65 (3H, m), 7.70-7.84 (2H,m), 7.96-8.06 (1H, m), 8.06-8.16 (1H, m);

MS (ES+) m/z 388.

EXAMPLE 110

(2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.30-1.54 (1H, m), 1.70-2.15 (4H, m),2.55-2.75 (1H, m), 2.75-2.94 (1H, m), 3.22-3.36 (1H, m), 3.36-3.53 (1H,m), 4.17-4.45 (2H, m), 6.62 (1H, d, J=15.2 Hz), 7.25-7.45 (3H, m),7.65-7.85 (3H, m), 7.96-8.19 (2H, m);

MS (ES+) m/z 372.

EXAMPLE 111

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.31-1.60 (1H, m), 1.72-2.19 (4H, m),2.56-3.25 (2H, m), 3.25-3.58 (2H, m), 4.18-4.40 (1H, m), 4.52-4.65 (2H,m), 6.62 (1H, d, J=15.2 Hz), 7.09-7.19 (1H, m), 7.34-7.46 (2H, m),7.65-7.88 (2H, m), 7.96-8.20 (2H, m);

MS (ES+) m/z 360.

EXAMPLE 112

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidetrihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (1H, m), 1.80-2.05 (3H, m),2.86-3.03 (1H, m), 3.03-3.20 (1H, m), 3.28-3.45 (1H, m), 3.45-3.57 (1H,m), 4.25-4.38 (1H, m), 4.51 (2H, s), 6.61 (1H, d, J=15.3 Hz), 7.40 (1H,d, J=15.2 Hz), 7.50 (1H, dd, J=7.0, 5.4 Hz), 7.66 (1H, d, J=7.7 Hz),7.85 (1H, br peak), 7.90-7.98 (1H, m), 8.02 (1H, s), 8.10 (1H, s), 8.65(1H, d, J=4.6 Hz);

MS (ES+) m/z 355.

EXAMPLE 113

(2E)-N-hydroxy-3-(5-{[(3R)-1-(4-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidetrihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.34-1.59 (1H, m), 1.74-2.19 (3H, m),2.61-2.84 (1H, m), 2.84-3.01 (1H, m), 3.25-3.46 (1H, m), 3.46-3.60 (1H,m), 4.30-4.50 (1H, m), 4.50-4.70 (2H, m), 6.62 (1H, d, J=15.3 Hz), 7.39(1H, d, J=15.2 Hz), 7.30 (1H, br peak), 8.01 (1H, s), 8.07-8.22 (3H, m),8.94 (2H, d, J=5.9 Hz);

MS (ES+) m/z 355.

EXAMPLE 114

(2E)-N-hydroxy-3-(5-{[(3R)-1-(3-pyridinylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidetrihydrochloride

¹H-NMR (300 MHz, DMSO-d6) (1.35-2.15 (4H, m), 2.56-3.80 (4H, m),4.45-4.70 (3H, m), 6.61 (1H, d, J=15.2 Hz), 7.39 (1H, d, J=15.2 Hz),7.80 (1H, br peak), 7.90-7.98 (1H, m), 8.01 (1H, s), 8.13 (1H, s),8.55-8.72 (1H, m), 8.90 (1H, d, J=5.0 Hz), 9.02-9.12 (1H, m), 11.59 (1H,br peak);

MS (ES+) m/z 355.

EXAMPLE 115(2E)-N-hydroxy-3-(5-{[(3R)-1-(3-thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.31-1.54 (1H, m), 1.70-2.15 (3H, m),2.54-3.21 (2H, m), 3.21-3.55 (2H, m), 4.20-4.43 (3H, m), 6.61 (1H, d,J=15.5 Hz), 7.30-7.45 (2H, m), 7.59-7.70 (1H, m), 7.70-85 (2H, m),7.96-8.08 (1H, m), 8.08-8.17 (1H, m);

MS (ES+) m/z 360.

EXAMPLE 116

(2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.87-2.16 (1H, m), 2.16-2.60 (1H, m),2.96-3.11 (1H, m), 3.11-4.10 (3H, m), 4.32-4.51 (2H, m), 4.57 (1H, brpeak), 6.63 (1H, d, J=15.2 Hz), 7.22 (2H, t-like, J=8.8 Hz), 7.39 (1H,d, J=15.2 Hz), 7.67 (2H, t-like, J=6.7 Hz), 7.90-8.16 (2H, m), 8.21 (1H,br peak); MS (ES+) m/z 358.

EXAMPLE 117

(2E)-3-(5-{[(3R)-1-(cycloheptylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.11-1.31 (2H, m), 1.31-1.69 (8H, m),1.69-1.84 (2H, m), 1.84-2.06 (3H, m), 2.56-2.78 (1H, m), 2.78-3.09 (3H,m), 3.09-4.00 (4H, m), 4.30 (1H, br peak), 6.62 (1H, d, J=15.4 Hz), 7.40(1H, d, J=15.4 Hz), 7.73-7.85 (1H, m), 7.98-8.10 (1H, m), 8.15 (1H, s),9.52 (1H, br peak);

MS (ES+) m/z 374.

EXAMPLE 118

(2E)-3-(5-{[(3R)-1-cycloheptyl-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.30-2.25 (16H, m), 2.57-3.50 (5H, m),4.24-4.40 (1H, m), 6.64 (1H, d, J=15.2 Hz), 7.40 (1H, d, J=15.2 Hz),7.75 (1H, br peak), 7.98-8.10 (1H, m), 8.10-8.17 (1H, m);

MS (ES+) m/z 360.

EXAMPLE 119

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.94-2.16 (1H, m), 2.16-2.70 (1H, m),2.96-3.14 (2H, m), 3.14-4.10 (6H, m), 4.41-4.61 (1H, m), 6.64 (1H, d,J=15.2 Hz), 7.23-7.50 (5H, m), 8.05 (1H, s), 8.11-8.24 (1H, m);

MS (ES+) m/z 354.

EXAMPLE 120

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.45-1.72 (2H, m), 1.76-1.94 (1H, m),1.94-2.10 (1H, m), 3.20-3.44 (2H, m), 3.88-4.04 (1H, m), 4.15-4.26 (1H,m), 4.42 (1H, dd, J=12.6, 3.4 Hz), 6.60 (1H, d, J=15.3 Hz), 6.68 (1H, t,J=4.8 Hz), 7.38 (1H, d, J=15.2 Hz), 7.80 (1H, br peak), 8.04 (1H, s),8.13 (1H, s), 8.40 (1H, d, J=4.8 Hz);

MS (ES+) m/z 342.

EXAMPLE 121

(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.44-1.64 (1H, m), 1.76-2.20 (3H, m),2.68-3.17 (2H, m), 3.17-3.41 (4H, m), 3.41-3.54 (1H, m), 3.54-3.65 (1H,m), 4.05-4.24 (1H, m), 4.24-4.41 (1H, m), 6.58-6.69 (1H, m), 7.14-7.31(4H, m), 7.40 (1H, d, J=15.4 Hz), 7.99-8.11 (1H, m), 8.18 (1H, s);

MS (ES+) m/z 380.

EXAMPLE 122

(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.01-1.35 (3H, m), 1.35-1.54 (2H, m),1.54-1.69 (1H, m), 1.72-1.89 (2H, m), 1.94-2.36 (4H, m), 3.02-4.10 (5H,m), 4.50-4.70 (1H, m), 6.75-7.07 (2H, m), 7.94-8.08 (1H, m), 8.26 (1H,s); MS (ES+) m/z 349.

EXAMPLE 123

To a solution of(2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(274 mg) in methanol (6.6 mL) was added hydrogen chloride in methanol(0.659 mL). After stirring at room temperature for 1 hour, the reactionmixture was evaporated in vacuo and triturated with ethyl acetate togive(2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride (252 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 1.01-4.59 (18H, m), 6.63 (1H, d, J=16 Hz),7.40 (1H, d, J=16 Hz), 8.01-8.19 (2H, m).

MS (ES+) m/z 332 (M+1).

The following compounds were obtained in a similar manner to that ofExample 123.

EXAMPLE 124

(2E)-3-(2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.93-4.67 (9H, m), 6.37 (1H, d, J=16 Hz),7.32 (1H, d, J=16 Hz), 7.41-7.65 (5H, m), 8.56 (2H, s).

MS (ES+) m/z 340 (M+1).

EXAMPLE 125(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-6-methyl-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.01-4.83 (12H, m), 6.64 (1H, d, J=16 Hz),7.18-7.27 (1H, m), 7.37 (1H, d, J=16 Hz), 7.42-7.51 (3H, m), 7.59-7.68(2H, m), 8.03 (1H, s).

MS (ES+) m/z 354 (M+1).

EXAMPLE 126

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.02-4.76 (9H, m), 6.74-6.83 (1H, m),7.28-7.69 (7H, m), 7.84-7.97 (1H, m), 10.2 (1H, brs), 11.4 (1H, brs).

MS (ES+) m/z 340 (M+1).

EXAMPLE 127

(2E)-N-hydroxy-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.04-2.16 (1H, m), 2.33-2.46 (1H, m),3.29-4.65(5H, m), 6.42 (1H, d, J=16 Hz), 6.56-6.68 (3H, m), 7.12-7.24(3H, m), 7.49 (1H, d, J=16 Hz), 8.06-8.13 (1H, m), 8.23 (1H, brs).

MS (ES+) m/z 323 (M−1).

EXAMPLE 128

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.88-1.02 (2H, m), 1.09-4.79 (18H, m),6.76-6.85 (1H, m), 7.35-7.56 (2H, m), 7.89-7.98 (1H, m), 10.6 (1H, brs).

MS (ES+) m/z 346 (M+1).

EXAMPLE 129

2M ethanolic hydrogen chloride (2.0 mL) was added to the solution of(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(0.5 g) in EtOH (5 ml) and the mixture was stirred at ambienttemperature for 3 hrs. To the reaction mixture was added AcOEt andisolated precipitate was collected by filtration to give(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride (0.28 g),

(+)ESI-MS: 411(M+H)+.

The following compounds were obtained in a similar manner to that ofExample 129.

EXAMPLE 130

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR(DMSO-d6): δ 0.81-1.40(6H, m), 1.49-2.62(8H, m), 2.97-4.09(5H, m),4.37-4.66(1H, m), 6.49-6.50(total 1H, each d, J=each 15.2 Hz), 7.09(1H,s), 7.20(1H, d, J=15.2 Hz),

(+)ESI-MS: 351(M+H)+.

EXAMPLE 131

(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR(DMSO-d6): δ 1.48-2.09(4H, m), 2.66-3.42(4H, m), 4.31-4.47(2H, m),4.62 and 4.75(total 1H, each s), 6.78 and 6.81(total 1H, each d, J=each39.8 Hz), 6.94(1H, d, J=6.3 Hz), 7.43-7.50(3H, m), 7.62-7.74(2H, m),7.88 and 7.90(total 1H, each d, J=each 1.9 Hz), 8.26 and 8.28(total 1H,each d, J=each 1.9 Hz), 11.34 and 11.66(total 1H, each s),

(+)ESI-MS: 405(M+H)+.

EXAMPLE 132

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

(+)ESI-MS: 383(M+H)+.

EXAMPLE 133

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

(+)ESI-MS: 397(M+H)+.

EXAMPLE 134

(2Z)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

(+)ESI-MS: 371(M+H)+.

EXAMPLE 135

(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR(DMSO-d6): δ 0.89-1.02(2H, m), 1.06-1.30(3H, m), 1.44-2.16(10H,m), 2.75-3.67(6H, m), 4.41 and 4.67(total 1H, each s), 6.87 and6.89(total 1H, each d, J=each 39.2 Hz), 7.04-7.14(1H, m), 8.01-8.11(1H,m), 8.20-8.29(1H, m),

(+)ESI-MS: 377(M+H)+.

EXAMPLE 136

(2Z)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR(DMSO-d6): δ 1.45-2.15(12H, m), 2.79-3.09(2H, m), 3.34-3.66(3H,m), 4.31 and 4.67(total 1H, each s), 6.88 and 6.89(total 1H, each d,J=each 39.1 Hz), 7.07-7.15(1H, m), 8.04-8.13(1H, m), 8.20-8.30(1H, m),

(+)ESI-MS: 349(M+H)+.

EXAMPLE 137

(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR(DMSO-d6): δ 1.02-1.66(7H, m), 1.74-2.26(7H, m), 2.82-3.59(5H, m),4.41 and 4.69(total 1H, each s), 6.89 and 6.90(total 1H, each d, J=each39.0 Hz), 7.09-7.18(1H, m), 8.05-8.14(1H, m), 8.21 and 8.27(total 1H,each s)

(+)ESI-MS: 363(M+H)+.

EXAMPLE 138

A mixture of(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(185 mg) and 2NHCl/EtOH (9 ml, 20 eq.) was stirred at room temperaturefor 3 hours. After then, IPE (50 ml) was added and stirred. Precipitatewas filtered, washed with IPE, and dried to give 486 mg (95%) of(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)-N-hydroxyacrylamidedihydrochloride as a powder.

MASS (ESI+): m/z=339.13 (M+1).

¹HNMR (400 MHz, DMSO-d6): δ 1.90-2.10 (2H, m), 2.25-2.60 (2H, m),3.10-3.40 (2H, m), 4.31 (1H, br.s), 4.42 (2H, d, J=6.0 Hz), 6.74 (1H, d,J=13.9 Hz), 7.44 (5H, s), 7.64 (2H, m), 7.80 (1H, m), 8.07 (d, 13.9 Hz).

EXAMPLE 139

To a solution of(2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(240 mg) in ethanol (3.6 mL) was added 2N HCl-EtOH (10.1 mL), which wasstirred at room temperature for 1 hour. To the resultant was added ethylacetate (9.6 mL), which was stirred for 1 hour. The precipitate wasfiltered to give(2E)-N-hydroxy-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride (223 mg) as a yellow powder.

¹H NMR (400 MHz, DMSO-d6) δ 1.94-2.58 (2H, m), 2.96-5.02 (10H, m), 6.63(1H, dd, J=2.6, 15.2 Hz), 6.99 (1H, d, J=8.2 Hz), 7.15 (1H, d, J=6.4Hz), 7.26-7.45 (3H, m), 8.00-8.34 (3H, m), 11.32 (1H, br);

MS (ES+) m/z 370 (M+1).

The following compounds were obtained in a similar manner to that ofExample 139.

EXAMPLE 140

(2E)-3-(5-{[(3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.19-2.40 (2H, m), 3.01-3.82 (4H, m),3.95-5.05 (3H, m), 6.29 (1H, dd, J=2.5, 15.3 Hz), 7.39 (1H, d, J=15.3Hz), 7.67 (1H, dt, J=1.8, 7.8 Hz), 7.93 (1H, d, J=7.9 Hz), 7.96-8.11(3H, m), 8.11-8.38 (2H, m), 11.45-11.64 (1H, m);

MS (ES+) 365 (M+1).

EXAMPLE 141

(2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.92-2.39 (5H, m), 2.97-3.79 (4H, m),3.81-4.68 (3H, m), 6.63 (1H, dd, J=2.9, 15.4 Hz), 7.23-7.45 (3H, m),7.53 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=9.0 Hz), 7.97-8.33 (3H, m), 10.18(1H, s), 11.0.4 (1H, br);

MS (ES+) m/z 397 (M+1).

EXAMPLE 142

(2E)-3-[5-({(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamidetrihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.92-2.84 (2H, m), 2.88-4.80 (13H, m), 6.65(1H, d, J=15.3 Hz), 6.83-7.55 (5H, m), 7.94-8.36 (3H, m), 11.32 (1H,br);

MS (ES+) m/z 383 (M+1).

EXAMPLE 143

(2E)-N-hydroxy-3-(5-{[(3R)-1-{3-[(methylsulfonyl)amino]benzyl}-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.90-2.59 (2H, m), 3.08 (3H, s), 3.15-4.81(7H, m), 6.63 (1H, dd, J=2.8, 15.2 Hz), 7.21 (1H, dd, J=2.0, 7.2 Hz),7.32-7.47 (4H, m), 7.98-8.41 (3H, m), 9.9.8 (1H, s), 11.30 (1H, br); MS(ES+) m/z 433 (M+1).

EXAMPLE 144

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.94-2.43 (2H, m), 2.93-5.02 (10H, m), 6.60(1H, dd, J=3.3, 15.3 Hz), 6.96-7.07 (1H, m), 7.11 (1H, t, J=9.0 Hz),7.33-7.49 (2H, m), 7.50-7.61 (1H, m), 7.99-8.37 (3H, m), 10.72 (1H, br);

MS (ES+) m/z 369 (M+1).

EXAMPLE 145

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.92-2.59 (2H, m), 3.01-4.73 (7H, m), 6.63(1H, d, J=15.3 Hz), 6.81-6.93 (1H, m), 6.78 (1H, t, J=8.2 Hz), 7.26 (1H,t, J=7.5 Hz), 7.39 (1H, d, J=15.3 Hz), 7.42-7.51 (1H, m), 8.00-8.30 (2H,m), 10.22-10.69 (2H, m);

MS (ES+) m/z 356 (M+1).

EXAMPLE 146

(2E)-N-hydroxy-3-(5-{[(3R)-1-(3-hydroxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.93-2.40 (2H, m), 2.99-3.80 (4H, m),4.17-5.38 (3H, m), 6.63 (1H, dd, J=2.4, 15.2 Hz), 6.84 (1H, d, J=7.9Hz), 6.93-7.08 (2H, m), 7.22 (1H, dt, J=2.1, 7.8 Hz), 7.38 (1H, d,J=15.3 Hz), 7.98-8.45 (3H, m), 11.16 (1H, br),

MS (ES+) m/z 356 (M+1).

EXAMPLE 147

(2E)-N-hydroxy-3-(5-{[(3R)-1-(3-isopropoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H NMR (DMSO-d6, 400 MHz) δ 1.23-1.32 (6H, m), 1.94-2.56 (2H, m),2.95-3.29 (4H, m), 3.86-4.84 (4H, m), 6.63 (1H, dd, J=2.9, 15.3 Hz),6.95 (1H, dd, J=2.1, 8.1 Hz), 7.11 (1H, d, J=7.0 Hz), 7.21-7.49 (3H, m),7.98-8.45 (3H, m), 11.35 (1H, br);

MS (ES+) m/z 398 (M+1).

EXAMPLE 148

A mixture of(2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(600 mg) and 2N HCl/Ethanol (13.6 ml, 20 eq) was stirred at roomtemperature for 2 hours. After then, ethyl acetate (10 ml) and IPE (50ml) was added and stirred. Precipitate was filtered, washed with IPE,and dried under reduced pressure to give 486 mg (83%) of(2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride as a powder.

MASS (ESI+): m/z=358.3(M+1).

¹HNMR (400 MHz, DMSOd6, δ): δ 1.96-2.37 (2H, m), 3.05-3.85 (4H, m), 4.47(1H, d, J=5.5 Hz), 4.51 (1H, d, J=5.5 Hz), 4.59 (m, 1H), 6.63 (1H, dd,J=2.6 Hz and 15.1 Hz), 7.28-7.39 (2H, m), 7.39 (1H, d, J=15.1 Hz),7.49-7.56 (1H, m), 7.72-7.79 (1H, m) 8.02 (1H, d, J=8.3 Hz), 8.14 (1H,s), 11.12 (1H, br.s).

EXAMPLE 149

A mixture of(2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(700 mg) and 2N HCl/Ethanol (16.4 ml) was stirred for 2 hrs.

EtOAc (10 ml) and IPE (50 ml) was added and and stirred. After 1 hr,precipitate was filtered and dried to give 565 mg of(2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride as a powder.

MASS (ESI+): m/z=358.3 (M+1).

¹HNMR (400 MHz, CDCl₃): δ 1.96-2.56 (2H, m), 3.03-3.80 (4H, m), 4.43(1H, d, J=5.7 Hz), 4.49 (1H, d, J=5.7 Hz), 4.60 (m, 1H), 6.63 (1H, dd,J=2.2 Hz and 15.3 Hz), 7.25-7.32 (1H, m), 7.39 (1H, d, J=15.3 Hz),7.46-7.54 (2H, m), 7.59 (1H, d, J=10.0 Hz), 8.03, 8.10 (1H, s), 8.14(1H, s), 11.48-11.73 (1H, m).

EXAMPLE 150

i) To a solution of tert-butyl[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate(128 mg) in methanol (2.5 mL) was added hydrogen chloride in methanol(0.248 mL). After stirring at room temperature for 1 hour, the reactionmixture was evaporated in vacuo.

ii) To a mixture of above product and dioxane (2.5 mL) was added 4Nhydrogen chloride in dioxane (1.02 mL). After stirring at roomtemperature for 2 hours, the reaction mixture was evaporated in vacuoand triturated with ethyl acetate to give(2E)-3-(6-{[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride (92.0 mg).

¹H-NMR (300 MHz, DMSO-d6) δ 0.85 (6H, t, J=7 Hz), 1.28-1.52 (4H, m),1.58-1.72 (1H, m), 2.02-2.15 (1H, m), 2.32-2.67 (2H, m), 3.06-4.78 (6H,m), 6.37 (1H, d, J=16 Hz), 6.91-7.08 (1H, m), 7.43 (1H, d, J=16 Hz),7.94-8.02 (1H, m), 8.21 (1H, brs), 10.4 (1H, brs).

MS (ES+) m/z 333 (M+1).

The following compounds were obtained in a similar manner to that ofExample 150.

EXAMPLE 151

(2E)-3-(6-{[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.87-4.62 (15H, m), 6.23 (1H, d, J=16 Hz),6.57 (1H, d, J=8 Hz), 7.15-7.69 (5H, m), 8.15 (1H, brs), 8.93 (1H, brs),10.7 (1H, brs), 11.0 (1H, brs).

MS (ES+) m/z 367 (M+1).

EXAMPLE 152

(2E)-N-hydroxy-3-(6-{[(3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.01-4.75 (11H, m), 6.33-6.42 (1H, m),6.96-7.07 (4H, m), 7.29-7.47 (3H, m), 7.92-8.01 (1H, m), 8.21 (1H, brs).

MS (ES+) m/z 3.69 (M+1).

EXAMPLE 153

(2E)-3-(6-{[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.91 (3H, t, J=7 Hz), 1.26-1.40 (2H, m),1.57-1.71 (2H, m), 1.95-4.73 (9H, m), 6.37 (1H, d, J=16 Hz), 6.90-7.07(1H, m), 7.43 (1H, d, J=16 Hz), 7.93-8.02 (1H, m), 8.21 (1H, brs).

MS (ES+) m/z 305 (M+1).

EXAMPLE 154

(2E)-N-hydroxy-3-(6-{[(3R)-1-isobutyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.00 (6H, d, J=7 Hz), 1.95-2.15 (2H, m),2.31-2.60 (2H, m), 3.02-4.76 (6H, m), 6.37 (1H, d, J=16 Hz), 6.90-7.08(1H, m), 7.43 (1H, d, J=16 Hz), 7.93-8.02 (1H, m), 8.21 (1H, brs), 10.4(1H, brs).

MS (ES+) m/z 305 (M+1).

EXAMPLE 155

To a solution of ethyl(2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)acrylate(200 mg, 0.50 mmol) in methanol (5 mL) was added hydroxylaminehydrochloride (175 mg, 2.52 mmol) at ambient temperature under nitrogen.After cooling, 1M sodium methanolate in methanol (5 mL) was addeddropwise to the mixture over 1 h, the reaction mixture was stirred at 0°C. for 2 hrs and at ambient temperature for 4 hrs. The reaction mixturewas adjusted to PH 6.0 with 1 mol/L hydrochloric acid and evaporated invacuo. The residue was dissolved in ethanol and the precipitate wasremoved by filtration. The solvent was evaporated in vacuo. The residuewas purified by preparative HPLC (CH₃CN, 20% NH₄HCO₃/30%-90%, gradient)to give(2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide(15 mg, 8%) as a powder.

¹H-NMR (300 MHz, CD₃OD) δ 1.78-1.98 (1H, m), 1.98-2.15 (1H, m),2.44-2.74 (2H, m), 3.40 (1H, dd, J=11.4, 5.9 Hz), 3.76 (1H, dd, J=11.4,4.0 Hz), 4.31 (1H, br peak), 4.93 (2H, s), 6.66 (1H, d, J=15.4 Hz),7.20-7.33 (3H, m), 7.33-7.43 (2H, m), 7.48 (1H, d, J=15.4 Hz), 7.94 (1H,s), 8.03 (1H, s);

MS (ES+) m/z 384.

The following compounds were obtained in a similar manner to that ofExample 129.

EXAMPLE 156

(2E)-N-hydroxy-3-(5-{[(3R)-1-(phenylacetyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamidehydrochloride

¹H-NMR (300 MHz, CD₃OD) δ 1.19-2.21 (4H, m), 3.12-3.49 (2H, m),3.70-4.01 (4H, m), 4.24-4.35 (1H, m), 6.76-6.90 (1H, m), 7.09-7.41 (5H,m), 7.48-7.58 (1H, m), 8.01 (0.6H, br.s), 8.06 (0.4H, br.s), 8.18 (0.4H,br.s), 8.45 (0.6H, br.s).

EXAMPLE 157

(2E)-N-hydroxy-3-(5-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.90-2.15 (1H, m), 2.31 (1.5H, s), 2.33(1.5H, s), 2.98-3.80 (5H, m), 4.30-4.66 (3H, m), 6.58-6.68 (1H, m),7.21-7.46 (5H, m), 8.00-8.35 (3H, m);

MS (ES+) m/z 354(M+1, free).

EXAMPLE 158

(2E)-N-hydroxy-3-(6-{[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidetrihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.43 (3H, s), 1.49 (9H, s), 1.78-2.32 (6H,m), 3.04-4.85 (6H, m), 6.32-6.46 (1H, m), 6.86-7.27 (1H, m), 7.39-7.52(1H, m), 7.91-8.12 (1H, m), 8.14-8.35 (2H, m), 9.51-9.78 (1H, m);

MS (ES+) m/z 388(M+1, free).

EXAMPLE 159

(2E)-N-hydroxy-3-(6-{[(3R)-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.61-1.86 (2H, m), 1.87-2.41 (8H, m),3.06-4.21 (5H, m), 4.49-4.73 (1H, m), 6.36 (1H, d, J=16.1 Hz), 6.84-7.09(1H, m), 7.43 (1H, d, J=16.1 Hz), 7.89-8.05 (1H, m), 8.21 (1H, s);

MS (ES+) m/z 333(M+1, free).

EXAMPLE 160

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.84-1.05 (2H, m), 1.07-1.34 (4H, m),1.52-2.05 (9H, m), 2.67-3.10 (4H, m), 3.40-3.58 (2H, m), 6.35 (1H, d,J=15.8 Hz), 6.87 (1H, br.d, J=6.6 Hz), 7.36 (1H, d, J=15.8 Hz), 7.90(1H, br.s), 8.22 (1H, br.s);

MS (ES+) m/z 393(free, M+1).

EXAMPLE 161

A solution of 2N HCl-EtOH solution (1.2 ml) was added to a mixture of(2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(200 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (30ml) was added to a reaction mixture and the resultant mixture wasstirred at ambient temperature for 20 minutes. The precipitate wascollected by filtration to give(2E)-3-(2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl)-N-hydroxyacrylamidedihydrochloride (90 mg).

¹H-NMR (DMSO-d6): δ 1.70-20.7 (1H, m), 2.10-2.42 (1H, m), 2.42 (3H, s),3.10-3.77 (4H, m), 4.42 (2H, s), 4.57-4.70 (1H, m), 6.34 (1H, d J=15.80Hz), 7.39-7.46 (4H, m), 7.62-7.65 (2H, m), 8.49 (1H, s), 11.40-11.58(1H, m).

The following compounds were obtained in a similar manner to that ofExample 161.

EXAMPLE 162

(2E)-3-{2-[(1-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinyl}-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 1.86-2.13 (4H, m), 2.46 (3H, s), 2.78-3.49 (4H, m),4.03 (1H, m), 4.29 (2H, d J=4.42 Hz), 6.37 (1H, d J=15.82 Hz), 7.41 (1H,d J=15.82 Hz), 7.44-7.47 (3H, m), 7.65-7.68 (2H, m), 8.15-8.25 (1H, m),8.50 & 8.53 (total 1H, each s).

EXAMPLE 163

(2E)-N-hydroxy-3-(4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 1.80-2.46 (2H, m), 2.32 (3H, s), 2.49 (3H, s),3.04-3.74 (4H, m), 4.35 (2H, s), 4.55-4.68 (1H, m), 6.33 (1H, d J=15.78Hz), 7.25 (2H d J=7.12 Hz), 7.39-7.62 (3H, m), 8.48 (1H, s).

EXAMPLE 164

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 0.90-1.26 (6H, m), 1.65-2.09 (6H, m), 2.10-2.30 (1H,m), 2.43 (3H, s), 2.98-3.88 (5H, m), 3.88-3.91 (1H, m), 4.59-4.70 (1H,m), 6.34 (1H, d J=15.78 Hz), 7.43 (1H, d J=15.78 Hz), 8.01-8.10 (1H, m),8.49 (1H, s), 10.54-10.64 (1H, m).

EXAMPLE 165

A solution of tert-butyl(3R)-3-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]-1-pyrrolidinecarboxylate(450 mg) and pyridinium p-toluenesulfonate (261 mg) in EtOH (10 ml) wasstirred at 55-60° C. for 9 hours. The reaction mixture was evaporated invacuo and the residue was dissolved in a mixture of AcOEt and H₂O andadjusted to was adjusted to PH10 with aq.K₂CO₃ solution. The aqueoussolution was adjusted to PH6.5 with aq.HCl solution and extracted withAcOEt. The extract was washed with brine and dried over MgSO₄. Thesolvent was evaporated in vacuo and the residue was washed with IPE togive tert-butyl(3R)-3-({5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate(118 mg).

¹H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.69-1.84 (1H, m), 1.99-2.12 (1H, m),3.09-3.14 (1H, m), 3.34-3.43 (2H, m), 3.52-3.66 (1H, m), 4.01-4.05 (1H,m), 6.19 (1H, d J=15.88 Hz), 6.50 (1H, d J=8.38 Hz), 7.26 (1H, d J=6.62Hz), 7.34 (1H, d J=15.88 Hz), 7.61 (1H, d J=8.38 Hz), 8.16 (1H, s), 8.91(1H, s), 10.59 (1H, s).

EXAMPLE 166

A solution of 2N HCl-EtOH solution (2.3 ml) was added to a mixture of(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(440 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours.

IPE (20 ml) was added to a reaction mixture and the resultant mixturewas stirred at ambient temperature for 20 minutes. The precipitate wascollected by filtration to give(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)₇N-hydroxyacrylamidedihydrochloride (375 mg).

¹H-NMR (DMSO-d6): 1.92-2.25 (2H, m), 2.32 (3H, s), 307-3.67 (4H, m),4.35 (2H, d J=5.30 Hz), 4.71 & 4.90 (total 1H, each br, s), 6.39 (1H, dJ=15.80 Hz), 7.22-7.45 (5H, m), 7.83 (1H, s), 8.21 (1H, s).

The following compounds were obtained in a similar manner to that ofExample 166.

EXAMPLE 167

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 1.78-2.09 (8H, m), 2.73 (1H, m), 304-3.80 (6H, m),4.46-4.52 (1H, m), 6.29 (1H, d J=15.60 Hz), 7.16-7.20 (1H, m), 7.24 (1H,d J=15.60 Hz), 7.91 (1H, s), 8.23 (1H, s).

EXAMPLE 168

(2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): 1.37-1.73 (6H, m), 1.92-2.09 (2H, m), 4.33-4.39 (1H,m), 6.40 (1H, d J=15.80 Hz), 7.37 (1H, d J=15.80 Hz), 8.03 (1H, s), 8.19(1H, s).

EXAMPLE 169

(2E)-3-{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 0.97 (9H, s), 0.97-1.45 (6H, m), 1.45-1.96 (3H, m),3.84-3.89 & 4.21 (total 1H, each m), 6.36 & 6.37 (total 1H, each dJ=15.66 Hz), 7.36 (1H, d J=15.66 Hz), 7.96 & 8.02 (total 1H, each s),8.17 & 8.21 (total 1H, each s).

EXAMPLE 170

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 0.91-1.27 (6H, m), 1.65-1.89 (5H, m), 2.09-2.10 (1H,m), 2.98-3.91 (6H, m), 4.79-4.91 (1H, m), 6.37 (1H, d J=15.78 Hz), 7.35(1H, d J=15.78 Hz), 7.91 (1H, s), 8.22 (1H, s), 10.64 (1H, br.s).

EXAMPLE 171

(2E)-3-(5-chloro-6-{[(3R)-1-(3-methyl-2-buten-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)N-hydroxyacrylamide dihydrochloride

¹H-NMR (DMSO-d6): δ 1.71 (3H, s), 1.77 (3H, s), 1.81-2.14 (2H, m),3.02-3.66 (4H, m), 3.75-3.81 (2H, m), 4.68 (1H, m), 5.30-5.34 (1H, m),6.36 (1H, d J=15.68 Hz), 7.05-7.15 (1H, m), 7.35 (1H, d J=15.68 Hz),7.91 (1H, s), 8.24 (1H, s).

EXAMPLE 172

(2E)-3-(5-chloro-6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 1.71-2.52 (2H, m), 3.06-4.71 (4H, m), 4.44 (2H, dJ=5.58 Hz), 4.70-4.89 (1H, m), 6.37 (1H, d J=15.80 Hz), 7.23-7.90 (5H,m), 7.94 (1H, d J=1.88 Hz), 8.21 (1H, d J=1.88 Hz).

EXAMPLE 173

(2E)-3-[5-chloro-6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.95-2.09 (2H, m), 2.39 (3H, s), 3.11-3.45 (3H, m),3.44-3.53 (1H, m), 4.30-4.36 (1H, m), 6.35 (1H, d J=15.76 Hz), 7.34 (1H,d J=15.76 Hz), 7.37 (2H, d J=8.16 Hz), 7.64 (2H, d J=8.16 Hz), 7.86 (1H,d J=1.36 Hz), 8.18 (1H; d J=1.36 Hz).

EXAMPLE 174

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.24-1.33 (6H, m), 1.66-2.52 (5H, m), 3.26-3.88 (4H,m), 4.51-4.67 (1H, m), 6.38 (1H, d J=15.68 Hz), 7.36 (1H, d J=15.68 Hz),7.94 (1H, s), 8.23 (1H, s).

EXAMPLE 175

(2E)-N-hydroxy-3-[6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.85-1.91 (1H, m), 2.07-2.14 (1H, m), 2.38 (3H, s),3.12-3.49 (4H, m), 4.33 (1H, br.s), 6.41 (1H, d J=15.82 Hz), 6.92 (1H, dJ=9.18 Hz), 7.38 (2H, d J=8.24 Hz), 7.44 (1H, d J=15.82 Hz), 7.67 (2H, dJ=8.24 Hz), 8.02 (1H, d J=9.18 Hz), 8.15 (1H, s), 9.10 (1H, m).

EXAMPLE 176

(2E)-N-hydroxy-3-(6-{[(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.50 (6H, br.s), 1.89-1.92 (1H, m), 2.18-2.22 (1H,m), 3.14 (4H, br.s), 3.14-3.54 (3H, m), 3.64-3.73 (1H, m), 4.76 (1H,br.s), 6.44 (1H, d J=15.84 Hz), 7.20 (1H, d J=9.36 Hz), 7.46 (1H, dJ=15.84 Hz), 8.09 (1H, d J=9.36 Hz), 8.18 (1H, s), 9.61 (1H, m).

EXAMPLE 177

(2E)-3-(5-chloro-6-{([(3R)-1-(1-piperidinylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.78 (6H, br.s), 1.82-2.10 (2H, m), 3.12 (4H, br.s),3.30-3.43 (3H, m), 3.54-3.63 (1H, m), 4.47-4.54 (1H, m), 6.36 (1H, dJ=15.76 Hz), 7.35 (1H, d J=15.76 Hz), 7.93 (1H, s), 8.21 (1H, s).

EXAMPLE 178

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.51-1.76 (8H, m), 1.90-2.30 (2H, m), 2.70-2.88 (1H,m), 3.28-3.68 (3H, m), 3.88-3.90 (1H, m), 4.50-4.69 (1H, m), 6.36 (1H, dJ=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.92 (1H, s), 8.23 (1H, s).

EXAMPLE 179

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.76-2.18 (9H, m), 3.26-3.68 (4H, m), 4.49-4.65 (1H,m), 6.35 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.90 (1H, s), 8.22(1H, s).

EXAMPLE 180

(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyridinylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidetrihydrochloride

¹H-NMR (DMSO-d6): δ 1.92-2.17 (1H, m), 2.18-2.35 (1H, m), 3.39-3.77 (4H,m), 4.66 (2H, s), 4.83 (1H, m), 6.41 (1H, d J=15.78 Hz), 7.54-7.60 (1H,m), 7.77-7.81 ( )1H, m), 7.92-7.09 (2H, m), 8.23 (1H, s), 8.70-8.73 (1H,m).

EXAMPLE 181

(2E)-3-(5-chloro-6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 1.97-2.22 (2H, m), 3.39-3.85 (4H, m), 4.52-4.66 (1H,m), 6.28-6.40 (1H, m), 7.29-7.39 (1H, m), 7.40-7.69 (5H, m), 7.88-7.96(1H, m), 8.16-8.25 (1H, m).

EXAMPLE 182

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 0.04-0.45 (2H, m), 0.56-0.65 (2H, m), 1.02-1.16 (1H,m), 2.08-2.13 (1H, m), 2.49-2.56 (1H, m), 2.02-3.93 (6H, m), 4.51-4.88(1H, m), 6.39 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.91 (1H, s),8.24 (1H, s), 11.12 (1H, br.s).

EXAMPLE 183

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 1.65-1.89 (5H, m), 2.06-2.13 (1H, m), 2.20-2.40 (1H,m), 2.98-3.92 (6H, m), 4.75-4.90 (1H, m), 6.37 (1H, d J=15.78 Hz), 7.35(1H, d J=15.78 Hz), 7.91 (1H, s), 8.22 (1H, s).

EXAMPLE 184

(2E)-3-(5-chloro-6-{[(3R)-1-(2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 2.18-2.39 (2H, m), 3.66-3.84 (3H, m), 3.95-4.04 (1H,m), 4.76-4.79 (1H, m), 6.39 (1H, d J=15.76 Hz), 6.92-6.98 (1H, m), 7.36(1H, d J=15.76 Hz), 7.92 (1H, s), 8.26 (1H, s), 8.60-8.63 (2H, m).

EXAMPLE 185

(2E)-3-(5-chloro-6-{[(3R)-1-(4-fluorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 2.09-2.22 (2H, m), 3.39-3.84 (4H, m), 4.55-4.67 (1H,m), 6.31 & 6.35 (total 1H, each d J=15.68 Hz), 7.00 (1H, m), 7.21-7.40(3H, m), 7.56-7.63 (2H, m), 7.87 & 7.91 (total 1H, each s), 8.16 & 8.24(total 1H, each s).

EXAMPLE 186

(2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 2.09-2.32 (2H, m), 2.32 & 2.35 (total 3H, each s),3.40-3.75 (4H, m), 4.53-4.66 (1H, m), 6.32 & 6.35 (total 1H, each dJ=15.76 Hz), 6.98 (1H, m), 7.29-7.73 (5H, m), 7.88 & 7.92 (total 1H,each s), 8.15 & 8.24 (total 1H, each s).

EXAMPLE 187

(2E)-3-(5-chloro-6-{[(3R)-1-(3-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 2.03-2.23 (2H, m), 3.43-3.76 (4H, m), 4.53-4.67 (1H,m), 6.33 & 6.36 (total 1H, each d J=15.74 Hz), 7.05 (1H, m), 7.27 & 7.36(total 1H, each d J=15.74 Hz), 7.45-7.58 (4H, m), 7.89 & 7.92 (total 1H,each s), 8.16 & 8.25(total 1H, each s).

EXAMPLE 188

(2E)-3-(5-chloro-6-{[(3R)-1-(2-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (DMSO-d6): δ 2.08-2.21 (2H, m), 3.15-3.22 (2H, m), 3.27-3.87 (2H,m), 4.55-4.65 (1H, m), 6.33 & 6.37 (total 1H, each d J=15.86 Hz), 6.93(1H, m), 7.27-7.55 (5H, m), 7.88 & 7.93 (total 1H, each s), 8.15 & 8.25(total 1H, each s).

EXAMPLE 189

To a stirred solution of tert-butyl(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl){(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}carbamate(80 mg) in methanol (1 mL) was added 4N hydrogen chloride in methanol (3mL) at ambient temperature and the mixture was stirred at the sametemperature for fifteen minutes. The mixture was concentrated in vacuoand the mixture was dissolved in dioxane (1 mL). To this solution wasadded 4N hydrogen chloride in dioxane (3 mL) and the mixture was stirredat ambient temperature for two hours. The reaction mixture wasconcentrated in vacuo and the resulting solid was triturated withacetonitrile to give(2E)-N-hydroxy-3-[6-({(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylamidedihydrochloride (40 mg) as a pale tan amorphous solid.

¹H-NMR (300 MHz, DMSO-d6) δ 1.10 (3H, s), 1.11 (3H, s), 1.35-1.49 (3H,m), 1.52-1.66 (3H, m), 1.73-1.86 (3H, m), 1.97-2.13 (2H, m), 3.09-4.22(6H, m), 4.57-4.86 (1H, m), 6.39 (1H, d, J=16.1 Hz), 6.92-7.23 (1H, m),7.39-7.54 (1H, m), 7.96-8.15 (1H, m), 8.16-8.27 (1H, m); MS (ES+) m/z385(free, M+1).

The following compound was obtained in a similar manner to that ofExample 189.

EXAMPLE 190

(2E)-N-hydroxy-3-(6-{[(3R)-1-(3,3,5,5-tetramethylcyclohexyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.93 (3H, s), 0.95 (3H, s), 0.97-1.12 (2H,m), 1.01 (6H, s), 1.20-1.36 (4H, m), 1.73-1.92 (2H, m), 1.95-2.16 (2H,m), 2.18-2.36 (1H, m), 2.46-3.62 (2H, m), 4.50-4.74 (1H, m), 6.37 (1H,d, J=15.4 Hz), 6.88-7.15 (1H, m), 7.44 (1H, d, J=15.4 Hz), 7.92-8.06(1H, m), 8.19-8.26 (1H, m); MS (ES+) m/z 387(M+1, free).

EXAMPLE 191

A solution of 2N HCl-EtOH solution (3.4 ml) was added to a mixture of(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(620 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (20ml) was added to a reaction mixture and the resultant mixture wasstirred at ambient temperature for 20 minutes. The precipitate wascollected by filtration to give(2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride (500 mg).

¹H-NMR (DMSO-d6): δ 1.52-1.55 (2H, m), 1.75-1.76 (4H, m), 1.97-2.09 (3H,m), 3.04-3.12 (1H, m), 3.20-3.81 (4H, m), 4.73.& 4.89 (total 1H, eachm), 6.79 (1H, dd J=3.08 Hz, 39.72 Hz), 7.27 (1H, m), 7.90 (1H, d J=1.80Hz), 8.30-8.32 (1H, m), 11.52 (1H, m).

The following compounds were obtained in a similar manner to that ofExample 191.

EXAMPLE 192

(2Z)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 1.04-1.25 (3H, m), 1.45-1.48 (2H, m), 1.58-1.62 (1H,m), 1.78-1.80 (2H, m), 2.04-2.10 (3H, m), 2.20-2.51 (1H, m), 3.10-3.15(2H, m), 3.26-3.46 (2H, m), 3.64 & 3.78 (total 1H, each m), 4.74 & 4.86(total 1H, each m), 6.79 (1H, dd J=2.48 Hz, 39.72 Hz), 7.20-7.30 (1H,m), 7.90 (1H, d J=1.56 Hz), 8.30-8.32 (1H, m), 11.29-11.36 (1H, m).

EXAMPLE 193

(2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 0.93-0.96 (2H, m), 1.03-1.25 (3H, m), 1.60-1.73 (4H,m), 1.86-1.91 (2H, m), 2.05-2.10 (1H, m), 2.30-2.50 (1H, m), 2.99-3.11(3H, m), 3.20-3.42 (1H, m), 3.52-3.60 (1H, m), 3.75 & 3.90-3.92 (total,1H, each m), 4.77 & 4.91 (total 1H, each m), 6.79 (1H, dd J=1.80 Hz,39.74 Hz), 7.21 & 7.41 (total 1H, each m), 7.90 (1H, d J=1.88 Hz),8.30-8.32 (1H, m), 10.71-10.72 (1H, m).

EXAMPLE 194

(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 2.05-2.07 (1H, m), 2.30-2.37 & 2.48-2.54 (total 1H,each m), 3.13-3.18 (1H, m), 3.32-3.68 (3H, m), 4.40 (2H, d J=5.64 Hz),4.71 & 4.90 (total 1H, each m), 6.78 (1H, dd J=3.20 Hz, 39.70 Hz), 7.27(1H, m), 7.44-7.48 (3H, m), 7.63-7.66 (2H, m), 7.89-7.91 (1H, m), 8.29(1H, m), 11.56-11.57 (1H, m).

EXAMPLE 195

(2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

¹H-NMR (DMSO-d6): δ 2.09-2.19 (1H, m), 2.32 & 2.62 (total 1H, each m),3.24-3.47 (2H, m), 3.57-3.82 (2H, m), 4.44 & 4.55 (total 2H, each dJ=5.68 Hz), 4.64 & 4.80 (total 1H, each m), 6.88 (1H, dd J=5.12 Hz,39.08 Hz), 7.00 & 7.20 (total 1H, each d J=9.24 Hz), 7.44-7.47 (3H, m),7.65-7.70 (2H, m), 8.03-8.09 (1H, m), 8.22 (1H, s), 11.52 & 11.65 (total1H, each br, s).

EXAMPLE 196

A mixture of(2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(530 mg) and 2N HCl/Ethanol (5 ml) was stirred for 3 hrs. EtOAc (10 ml)and IPE (50 ml) was added and and stirred. After 1 hour, precipitate wasfiltered and dried to give 462 mg (89%) of(2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride.

MASS (ESI+): m/z=450.9 (M+1).

¹HNMR (400 MHz, DMSO-d6): δ 0.90-2.80 (14H, m), 2.51 (6H, b.s), 3.2-3.8(4H, m), 4.52 and 4.66 (1H, br.s), 6.35 (1H, dd, J=4.9, 15.8 Hz),6.84-6.98 (1H, m), 7.34 (1H, d, J=15.8 Hz), 7.89 (1H, dd, J=1.8, 4.4Hz), 8.23 (1H, dd, J=1.8, 4.4 Hz).

EXAMPLE 197

A mixture of(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(680 mg) and 2N HCl/Ethanol (13.8 ml) was stirred for 2 hrs. EtOAc (10ml) and IPE (50 ml) was added and and stirred. After 1 hr, precipitatewas filtered and dried to give 387 mg (0.63%) of(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride.

MASS (ESI+): m/z=408.1 (M+1);

¹HNMR (400 MHz, CDCl₃): δ 0.82-2.27 (15H, m), 3.20-3.80 (4H, m), 4.51(1H, m), 4.61 (1H, m), 6.34 (1H, d, J=15.8 Hz), 7.34 (1H, d, J=15.8 Hz),7.90 (1H, s), 8.23 (1H, s).

EXAMPLE 198

(2E)-3-(5-fluoro-6-{[(3R)-1-(2-octyn-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidebis(4-methylbenzenesulfonate) (salt)

To a solution of(2E)-3-(5-fluoro-6-{[(3R)-1-(2-octyn-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(155 mg) in methanol (3.5 ml) was added 4-methylbenzenesulfonic acidhydrate (122 mg) at 25° C. and then stirred at the same temperature for1 hour. The mixture was concentrated under reduced pressure. Theresulting residue was triturated with a mixed solvent of ethyl acetate,diisopropyl ether and methanol. Title compound (178 mg, 73%) wasobtained as colorless powder.

MASS(API-ES); 375 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 0.84 (3H, t, J=6.8 Hz), 1.20-1.50 (6H,m), 2.00-2.60 (4H, m), 2.29 (6H, s), 3.00-4.05 (4H, m), 4.10-4.20 (2H,m), 4.63 (1H, br), 6.32 (1H, d, J=16 Hz), 7.12 (4H, d, J=7.9 Hz), 7.39(1H, d, J=16 Hz), 7.49 (4H, d, J=7.9 Hz), 7.70 (1H, d, J=13 Hz), 8.08(1H, s), 10.30 (1H, br).

The following compound was obtained in a similar manner to that ofExample 198.

EXAMPLE 199

(2E)-3-(5-fluoro-6-{[(3R)-1-(3-phenyl-2-propyn-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidebis(4-methylbenzenesulfonate) (salt)

MASS(API-ES); 381 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.65 (2H, m), 2.29 (6H, s),3.10-4.20 (4H, m), 4.48 (2H, br), 4.69 (1H, br), 6.32 (1H, d, J=16 Hz),7.12 (4H, d, J=7.8 Hz), 7.30-7.55 (11H, m), 7.60-7.80 (1H, m), 8.09 (1H,s), 10.51 (1H, br).

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 200

(2E)-3-(6-{[(3R)-1-acetyl-3-piperidinyl]amino}-5-chloro-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

MASS(ESI); 339 (M+H)+.

EXAMPLE 201(2E)-N-hydroxy-3-(5-{[(3R)-1-(1-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.63 (1.5H, d, J=6 Hz), 1.65 (1.5H, d, J=6Hz), 1.84-2.14 (1H, m), 2.30-2.53 (1H, m), 2.70-4.00 (4H, m), 4.32-4.68(2H, m), 6.61 (0.5H, d, J=15 Hz), 6.65 (0.5H, d, J=15 Hz), 7.31-7.53(4H, m), 7.61-7.73 (2H, m), 7.95-8.25 (3H, m), 11.63 (1H, br); MS (ES+)m/z 354.

EXAMPLE 202

(2E)-N-hydroxy-3-(5-{[2-(1-piperidinyl)phenyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.59 (2H, m), 1.76-1.91 (4H, m), 3.16-3.30(4H, m), 6.74 (1H, d, J=15.5 Hz), 7.21-7.38 (2H, m), 7.46 (1H, d, J=15.5Hz), 7.54 (1H, m), 7.85 (1H, dd, J=7.5, 1.5 Hz), 8.26 (1H, s), 8.39 (1H,s); MS (ES+) m/z 340.

The following compound(s) was(were) obtained in a similar manner to thatof Example 92.

EXAMPLE 203

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.85-1.32 (5H, m), 1.54-1.90 (6H, m), 2.05(1H, m), 2.22-2.54 (1H, m), 2.93-3.30 (3H, m), 3.34-4.72 (7H, m), 6.40(1H, d, J=16 Hz), 7.32 (1H, d, J=16 Hz), 8.06 (1H, m), 8.59 (2×1H, s),10.41 (1H, m); MS (ES+) m/z 346.

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 204

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 357 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.95-3.85 (4H, m),4.35-4.50 (2H, m), 4.55-4.75 (1H, m), 4.77 (2H, br), 6.31 (1H, d, J=16Hz), 7.30-7.80 (8H, m), 8.06 (1H, s), 11.31 (1H, br).

The following compounds were obtained in a similar manner to that ofExample 89.

EXAMPLE 205

(2E)-3-(6-{[(3R)-1-(2,2-difluoro-2-phenylethyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 407 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.95-2.60 (2H, m), 3.15-4.20 (4H, m),4.31 (2H, t, J=16 Hz), 4.50-4.85 (1H, m), 6.33 (1H, d, J=16 Hz), 7.39(1H, d, J=16 Hz), 7.50-7.80 (7H, m), 8.08 (1H, s), 11.28(1H, br).

EXAMPLE 206

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

MASS(API-ES); 359 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.10-1.40 (5H, m), 1.55-1.80 (5H, m),1.85-2.55 (3H, m), 3.25-3.95 (4H, m), 4.30-4.60 (1H, m), 6.40 (1H, d,J=16 Hz), 7.10 (1H, d, J=9.2 Hz), 7.45 (1H, d, J=16 Hz), 8.04 (1H, d,J=9.2 Hz), 8.20 (1H, s), 9.30 (1H, br), 10.90 (1H, br).

The following compound was obtained in a similar manner to that ofExample 41.

EXAMPLE 207

(2E)-3-(6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6): δ 1.85-1.40 (6H, m), 1.55-2.40 (12H, m),2.75-3.15 (4H, m), 3.20-4.30 (6H, m), 6.43 (1H, d, J=15.8 Hz), 7.14 (1H,d, J=9.3 Hz), 7.43 (1H, d, J=15.8 Hz), 8.03-8.18 (2H, m), 10.28 (1H,brs), 10.29 (1H, brs).

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 208

(2E)-3-(6-{[(3R)-1-benzoyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

MASS(API-ES); 353 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.80-2.40 (2H, m), 3.30-3.95 (4H, m),4.40-4.70 (1H, m), 6.40 (0.5H, d, J=16 Hz), 6.44 (0.5H, d, J=16 Hz),7.12 (0.5H, d, J=9.2 Hz), 7.23 (0.5H, d, J=9.2 Hz), 7.30-7.70 (6H, m),8.00-8.40 (2H, m), 9.48 (0.5H, br), 9.71 (0.5H, br), 10.90 (1H, br).

The following compound was obtained in a similar manner to that ofExample 41.

EXAMPLE 209

(2E)-3-(6-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 1.72 (3H, s), 1.78 (3H, s), 2.90-3.30 (2H, m),3.30-3.50 (2H, m), 3.55-3.80 (2H, m), 4.10-4.40 (1H, m), 5.37-5.44 (1H,m), 6.39 (1H, d, J=15.9 Hz), 7.35 (1H, d, J=15.9 Hz), 7.94 (1H, s), 8.19(1H, s).

Mass (APCI): 371(M+H)+.

The following compound was obtained in a similar manner to that of

EXAMPLE 129 EXAMPLE 210

(2E)-3-[6-(2,3-dihydro-1H-inden-2-ylamino)-3-pyridinyl]-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.95 (2H, dd, J=16.5, 5 Hz), 3.40 (2H, dd,J=16.5, 7 Hz), 4.64 (1H, m), 6.40 (1H, d, J=15.8 Hz), 7.05 (1H, d, J=10Hz), 7.16-7.24 (2H, m), 7.25-7.33 (2H, m), 7.46 (1H, d, J=15.8 Hz), 8.04(1H, d, J=10 Hz), 8.20 (1H, s), 9.38 (1H, br), 10.82 (1H, br); MS (ES+)m/z 296.

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 211

(2E)-3-(5-chloro-6-{[(3R)-1-cyclobutyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.90-1.90 (2H, m), 2.00-2.40 (5H, m),2.90-3.90 (5H, m), 4.69-4.86 (1H, m), 6.40 (1H, d, J=15.8 Hz), 7.22 (1H,brs), 7.50 (1H, d, J=15.8 Hz), 7.92 (1H, s), 8.23 (1H, s), 11.86 (1H,brs),

MASS(ESI); 337 (M+H)+.

EXAMPLE 212

(2E)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.40-1.60 (2H, m), 1.61-1.90 (4H, m),1.91-2.20 (4H, m), 3.06-3.82 (4H, m), 4.73-4.88 (1H, m), 6.37 (1H, d,J=15.8 Hz), 7.18 (1H, brs), 7.35 (1H, d, J=15.8 Hz), 7.91 (1H, s), 8.23(1H, s), 141.39 (1H, brs),

MASS(ESI); 351 (M+H)+.

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 213

(2E)-N-hydroxy-3-{4-[(6-methyl-2-pyridinyl)amino]phenyl}acrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.50 (3H, s), 6.43 (1H, d, J=16 Hz), 6.88(1H, d, J=7.5 Hz), 7.01 (1H, d, J=7.5 Hz), 7.45 (1H, d, J=16 Hz), 7.53(2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.83 (1H, dd, J=7.5, 7.5 Hz),10.12 (1H, br); MS (ES+) m/z 270.

The following compound was obtained in a similar manner to that ofExample 41.

EXAMPLE 214

(2E)-3-{5-chloro-6-[(1-methyl-4-piperidinyl)amino]-3-pyridinyl}-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 2.06 (4H, m), 2.71 (3H, d, J=4.6 Hz),3.04-3.49 (4H, m), 4.09-4.40 (1H, m), 6.40 (1H, d, J=15.8 Hz), 7.35 (1H,d, J=15.8 Hz), 7.95 (1H, s), 8.20 (1H, s), 10.88 (1H, brs),

MASS(ESI); 311 (M+H)+.

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 215

(2E)-3-(6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.48-1.78 (4H, m), 1.82-2.13 (2H, m), 4.00(1H, m), 4.30-4.60 (1H, m), 4.54 (2H, s), 6.32 (1H, d, J=16 Hz), 6.86(1H, br), 7.20-7.38 (6H, m), 7.88 (1H, s), 8.21 (1H, s); MS (ES+) m/z388.

The following compound was obtained in a similar manner to that ofExample 92.

EXAMPLE 216

(2E)-3-(6-{[(3R)-1-cycloheptyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.34-1.82 (10H, m), 1.94-2.16 (3H, m), 2.30(1H, m), 3.08-4.20 (5H, m), 4.57 (1H, m), 4.66 (1H, m), 6.38 (1H, d,J=15.5 Hz), 7.00 (1H, m), 7.44 (1H, d, J=15.5 Hz), 7.98 (1H, m), 8.21(1H, s), 10.26 (1H, br-s), 11.11 (1H, br); MS (ES+) m/z 345.

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 217

(2E)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.09-1.62 (7H, m), 1.78-2.07 (7H, m),2.84-3.46 (5H, m), 6.38 (1H, d, J=15.8 Hz), 6.77 (1H, d, J=7.6 Hz), 7.34(1H, d, J=15.8 Hz), 7.90 (1H, s), 8.23 (1H, s), 10.44 (1H, brs).

MASS(ESI); 379 (M+H)+.

EXAMPLE 218

(2E)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.56-1.99 (14H, m), 2.79-2.96 (1H, m),3.32-3.54 (3H, m), 6.38 (1H, d, J=15.8. Hz), 6.84 (1H, d, J=7.6 Hz),7.34 (1H, d, J=15.8 Hz), 7.90 (1H, s), 8.22 (1H, s), 10.71 (1H, brs),

MASS(ESI); 365 (M+H)+.

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 219

(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 358 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.95-3.85 (4H, m),4.35-4.70 (3H, m), 5.70 (2H, br), 6.69 (1H, d, J=25 Hz), 7.40-7.50 (3H,m), 7.60-7.70 (2H, m), 7.99 (0.5H, d, J=1.1 Hz), 8.06 (0.5H, d, J=1.1Hz), 8.33 (1H, s), 11.43 (1H, br).

The following compounds were obtained in a similar manner to that ofExample 129.

EXAMPLE 220

(2E)-3-(5-{[1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.78-0.97 (2H, m), 1.07-1.28 (3H, m),1.51-1.74 (6H, m), 1.85 (1H, m), 2.44 (1H, m), 2.96-3.12 (2H, m),3.25-3.40 (2H, m), 4.63 (1H, t, J=9 Hz), 6.61 (1H, d, J=15.5 Hz), 7.37(1H, d, J=15.5 Hz), 7.90 (1H, br), 8.07 (1H, s), 8.08 (1H, s); MS (ES+)m/z 360.

EXAMPLE 221

N-[2-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)phenyl]cyclohexanecarboxamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.13-1.54 (5H, m), 1.64 (1H, m), 1.69-1.86(4H, m), 2.42 (1H, m), 6.37 (1H, d, J=16 Hz), 7.14 (1H, ddd, J=7.5, 7.5,1.5 Hz), 7.21-7.30 (2H, m), 7.36 (1H, d, J=16 Hz), 7.78 (1H, d, J=7.5Hz), 8.02 (1H, d, J=1 Hz), 8.20 (1H, d, J=1 Hz), 8.32 (1H, s), 9.95 (1H,s); MS (ES+) m/z 415.

EXAMPLE 222

N-[2-({4-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]phenyl}amino)phenyl]cyclohexanecarboxamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.07-1.43 (5H, m), 1.55-1.78 (5H, m), 2.34(1H, m), 6.23 (1H, d, J=16 Hz), 6.81 (2H, d, J=8 Hz), 7.05 (1H, dd,J=7.5, 7.5 Hz), 7.12 (1H, dd, J=7.5, 7.5 Hz), 7.28 (1H, d, J=7.5 Hz),7.34 (1H, d, J=16 Hz), 7.37 (2H, d, J=8 Hz), 7.59 (1H, d, J=7.5 Hz),7.72 (1H, br), 9.25 (1H, s), 10.60 (1H, br); MS (ES+) m/z 380.

EXAMPLE 223

N-[3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)phenyl]cyclohexanecarboxamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.12-1.49 (5H, m), 1.59-1.84 (5H, m), 2.34(1H, m), 6.40 (1H, d, J=16 Hz), 7.16-7.34 (3H, m), 7.39 (1H, d, J=16Hz), 7.95 (1H, s), 8.03 (1H, s), 8.27 (1H, s), 8.65 (1H, s), 9.81 (1H,s); MS (ES+) m/z 415.

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 224

cyclopentyl(3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

¹H-NMR (200 MHz, DMSO-d6) δ: 1.40-1.90 (8H, m), 1.90-2.25 (4H, m),3.24-3.54 (3H, m), 3.57-3.66 (1H, m), 4.54 (1H, m), 4.99 (1H, brs), 6.23(1H, d, J=15.8 Hz), 6.91 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.89 (1H,s), 8.22 (1H, s),

MASS(ESI); 395 (M+H)+.

The following compound was obtained in a similar manner to that ofExample 41.

EXAMPLE 225

(2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.52-2.00 (4H, m), 2.73-2.92 (2H, m),2.24-3.59 (2H, m), 4.34 (2H, d, J=3.8 Hz), 4.58 (1H, brs), 6.37 (1H, d,J=15.8 Hz), 6.86 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.45-7.48 (3H, m),7.61-7.72 (2H, m), 7.88 (1H, s), 8.18 (1H, s), 11.15-11.52 (1H, brs),

MASS(ESI); 387 (M+H)+.

The following compound was obtained in a similar manner, to that ofExample 89.

EXAMPLE 226

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 363 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 0.80-1.40 (5H, m), 1.55-1.90 (6H, m),1.95-2.60 (2H, m), 2.90-4.10 (6H, m), 4.55-4.80 (1H, m), 4.82 (2H, br),6.33 (1H, d, J=16 Hz), 7.39 (1H, d, J=16 Hz), 7.60 (1H, br), 7.69 (1H,d, J=12 Hz), 8.07 (1H, s), 10.53 (1H, br).

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 227

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.58-1.77 (7H, m), 1.98-2.13 (2H, m),3.24-3.66 (4H, m), 4.54 (1H, m), 4.97 (1H, m), 6.34 (1H, d, J=15.8 Hz),6.92 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.89 (1H, s), 8.23 (1H, s),

MASS(ESI); 351 (M+H)+.

EXAMPLE 228

(2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.02-1.91 (14H, m), 2.62-3.07 (3H, m),3.80-4.25 (3H, m), 6.38 (1H, d, J=15.8 Hz), 6.69 (1H, brs), 7.36 (1H, d,J=15.8 Hz), 7.93 (1H, s), 8.19 (1H, s),

MASS(ESI); 407 (M+H)+.

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 229

(2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

MASS(API-ES); 377 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.10-1.45 (5H, m), 1.55-1.80 (5H, m),1.90-2.60 (2H, m), 3.20-3.90 (4H, m), 4.40-4.70 (1H, m), 5.40 (1H, br),6.33 (1H, d, J=16 Hz), 7.40 (1H, d, J=16 Hz), 7.75 (1H, d, J=13 Hz),7.80 (1H, br), 8.08 (1H, s).

The following compound was obtained in a similar manner to that ofExample 92.

EXAMPLE 230

(2E)-3-(6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.43-1.62 (2H, m), 1.64-1.84 (4H, m),1.90-2.16 (3H, m), 2.29 (1H, m), 3.10-4.05 (5H, m), 4.58 (1H, m), 4.70(1H, m), 6.38 (1H, d, J=16 Hz), 7.02 (1H, m), 7.44 (1H, d, J=16 Hz),8.00 (1H, m), 8.21 (1H, s), 10.26 (1H, s), 11.16-11.44 (1H, br); MS(ES+) m/z 317.

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 231

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, CD₃OD) δ 2.10-2.32 (1H, m), 2.40-2.75 (1H, m), 2.47(1.7H, s), 2.49 (1.3H, s), 3.23-3.45 (1H, m), 3.48-3.72 (2H, m), 3.84(0.6H, m), 4.00 (0.4H, m), 4.48-4.74 (3H, m), 6.73 (1H, d, J=15.5 Hz),6.74 (1H, d, J=15.5 Hz), 7.26-7.42 (3H, m), 7.44-7.58 (2H, m), 8.05-8.18(3H, m); MS (ES+) m/z 354.

The following compounds were obtained in a similar manner to that ofExample 89.

EXAMPLE 232

(2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 356 (M+H)+Free

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.70 (2H, m), 3.00-3.90 (4H, m),4.00-4.50 (3H, m), 6.26 (1H, d, J=16 Hz), 6.60-6.90 (1H, m), 7.20-7.39(3H, m), 7.40-7.50 (3H, m), 7.58-7.70 (2H, m), 11.10-11.50 (1H, m).

EXAMPLE 233

(2E)-3-(6-{[(3R)-1-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 393 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.95-2.70 (2H, m), 3.10-4.00 (4H, m),4.40-4.90 (3H, m), 6.31 (1H, d, J=16 Hz), 7.20-7.80 (6H, m), 8.07 (1H,s), 11.22 (1H, br).

EXAMPLE 234

(2E)-3-(5-fluoro-6-{[(3R)-1-(1,3-thiazol-2-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 364 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.60 (2H, m), 3.10-4.00 (4H, m),4.55-5.00 (3H, m), 6.34 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz), 7.56(1H, br), 7.69 (1H, d, J=13 Hz), 7.90-8.00 (2H, m), 8.07 (1H, s), 11.58(1H, br).

EXAMPLE 235

(2E)-3-(5-fluoro-6-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 371 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.95-2.60 (2H, m), 3.00-4.40 (8H, m),4.50-4.90 (1H, m), 6.32 (1H, d, J=16 Hz), 7.20-7.50 (6H, m), 7.52 (1H,br), 7.69 (1H, d, J=12 Hz), 8.06 (0.5H, s), 8.09 (0.5H, s), 11.00-11.30(1H, m).

EXAMPLE 236

(2E)-3-(5-fluoro-6-{[(3R)-1-(1-piperidinylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 392 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.20-1.90 (6H, m), 1.95-2.55 (2H, m),2.85-3.10 (2H, m), 3.30-4.35 (8H, m), 4.40-4.75 (1H, m), 6.35 (1H, d,J=16 Hz), 7.39 (1H, d, J=16 Hz), 7.58 (1H, br), 7.69 (1H, d, J=13 Hz),8.08 (1H, s), 9.65 (1H, br).

EXAMPLE 237

(2E)-3-[6-({(3R)-1-[(3-chloro-4-pyridinyl)methyl]-3-pyrrolidinyl}amino)-5-fluoro-3-pyridinyl]-N-hydroxyacrylamidetrihydrochloride

MASS(API-ES); 392 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.70 (2H, m), 3.10-4.05 (4H, m),4.60-5.00 (3H, m), 6.35 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz), 7.72(1H, d, J=12 Hz), 7.75 (1H, br), 8.00-8.10 (2H, m), 8.66 (1H, d, J=5.0Hz), 8.79 (1H, s), 11.80-12.10 (1H, m).

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 238

(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidetrihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.12 (1H, m), 2.44 (1H, m), 3.35-4.00 (4H,m), 4.59 (1H, m), 4.87 (2H, s), 6.64 (1H, d, J=15 Hz), 7.38 (1H, d, J=15Hz), 7.65-7.76 (2H, m), 7.84 (1H, ddd, J=7, 7, 1.5 Hz), 8.02-8.38 (6H,m), 8.50 (1H, d, J=8.5 Hz), 11.16 (1H, br-s); MS (ES+) m/z 391.

The following compound was obtained in a similar manner to that ofExample 92.

EXAMPLE 239

(2E)-3-(6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.02-1.52 (6H, m), 1.60 (1H, m), 1.73-1.86(2H, m), 1.94-2.14 (2H, m), 2.27 (1H, m), 3.04-4.05 (5H, m), 4.58 (1H,m), 6.34 (1H, d, J=16 Hz), 6.90 (1H, m), 7.42 (1H, d, J=16 Hz), 8.21(1H, s); MS (ES+) m/z 331.

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 240

(2E)-3-(6-{[(3R)-1-(1,3-benzothiazol-2-ylmethyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 414 (M+H)+Free,

¹H-NMR (400 MHz), (DMSO-d6, δ): 2.00-2.65 (2H, m), 3.20-4.10 (4H, m),4.60-5.10 (3H, m), 6.32 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz),7.50-7.75 (4H, m), 8.00-8.30 (3H, m), 11.50-11.90 (1H, m).

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 241

(2E)-3-(6-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (400 MHz, DMSO-d6) δ: 1.52 (1H, brs), 1.93-2.06 (3H, m),2.92-3.55 (4H, m), 4.34 (1H, brs), 4.50 (2H, s), 6.39 (1H, d, J=15.8Hz), 7.04 (1H, brs), 7.39-7.52 (3H, m), 7.57-7.60 (1H, m), 7.97-8.02(2H, m), 8.19 (1H, brs), 10.95 (1H, brs),

MASS(ESI); 387 (M+H)+.

EXAMPLE 242

(2E)-3-(6-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (400 MHz, DMSO-d6) δ: 1.46 (1H, brs), 1.81-2.08 (3H, m),2.89-3.52 (4H, m), 4.34 (1H, brs), 4.39-4.42 (1H, m), 6.42 (1H, d,J=15.8 Hz), 7.08-7.10 (1H, m), 7.42 (1H, d, J=15.8 Hz), 7.47-7.55 (3H,m), 7.62 (1H, d, J=6.8 Hz), 7.79 (1H, s), 8.06 (1H, brs), 8.20 (1H, s),11.08-11.22 (1H, m),

MASS(ESI); 387 (M+H)+.

EXAMPLE 243

(2E)-3-(6-{[(3R)-1-acetyl-3-piperidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

MASS(ESI); 323 (M+H)+.

The following compounds were obtained in a similar manner to that ofExample 129.

EXAMPLE 244

(2E)-3-(5-{[(3R)-1-(2,3-dihydro-1H-inden-2-yl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.00-2.40 (2H, m), 3.04-4.27 (9H, m), 4.52(0.5H, m), 4.60 (0.5H, m), 6.64 (1H, d, J=15 Hz), 7.18-7.32 (5H, m),7.40 (1H, d, J=15 Hz), 8.04 (0.5H, s), 8.06 (0.5H, s), 8.17 (1H, s),11.63 (1H, br); MS (ES+) m/z 366.

EXAMPLE 245

(2E)-3-{6-[(2-benzylphenyl)amino]-5-chloro-3-pyridinyl}-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 3.93 (2H, s), 6.35 (1H, d, J=16 Hz),7.07-7.32 (9H, m), 7.33 (1H, d, J=16 Hz), 7.45 (1H, d, J=8 Hz), 7.98(1H, d, J=1.5 Hz), 8.09 (1H, d, J=1.5 Hz), 8.31 (1H, s); MS (ES+) m/z380.

EXAMPLE 246

(2E)-3-(5-{[(3R)-1-(4-ethoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J=7 Hz), 2.00 (1H, m),2.21-2.53 (1H, m), 2.96-3.80 (4H, m), 4.03 (2H, q, J=7 Hz), 4.33 (2H,m), 4.44 (0.5H, m), 4.55 (0.5H, m), 6.62 (0.5H, d, J=15.5 Hz), 6.63(0.5H, d, J=15.5 Hz), 6.97 (1H, d, J=9 Hz), 6.98 (1H, d, J=9 Hz), 7.38(1H, d, J=15.5 Hz), 7.49 (1H, d, J=9 Hz), 7.50 (1H, d, J=9 Hz), 7.98(0.5H, br), 8.02 (0.5H, s), 8.04 (0.5H, s), 8.14 (1H, s), 8.16 (0.5H,br), 10.87 (1H, br); MS (ES+) m/z 384.

The following compounds were obtained in a similar manner to that ofExample 92.

EXAMPLE 247

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.92-2.17 (1H, m), 2.24-2.58 (1H, m), 3.05(0.5H, m), 3.15-3.42 (2H, m), 3.51 (0.5H, m), 3.63 (0.5H, m), 3.95(0.5H, m), 4.33-4.62 (3H, m), 7.01 (0.5H, d, J=15.5 Hz), 7.05 (0.5H, d,J=15.5 Hz), 7.33 (1H, d, J=15.5 Hz), 7.40-7.52 (3H, m), 7.60-7.71 (2H,m), 7.75 (0.5H, m), 7.92 (1H, s), 7.95 (0.5H, s), 7.96 (0.5H, m), 7.99(0.5H, s), 11.18 (0.5H, br), 11.31 (0.5H, br); MS (ES+) m/z 340.

EXAMPLE 248

(2E)-N-hydroxy-3-(2-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.95-2.16 (1H, m), 2.19-2.54 (1H, m),2.96-4.00 (8H, m), 4.58 (1H, m), 6.40 (1H, d, J=16 Hz), 7.23-7.42 (7H,m), 7.99 (0.5H, br), 8.13 (0.5H, br), 8.58 (1H, s), 8.59 (1H, s), 10.89(0.5H, br), 11.11 (0.5H, br); MS (ES+) m/z 354.

The following compounds were obtained in a similar manner to that ofExample 89.

EXAMPLE 249

(2Z)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-2-fluoro-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 358 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.95-3.90 (4H, m),4.35-4.70 (3H, m), 6.21 (2H, br), 6.70 (1H, d, J=39 Hz), 7.40-7.50 (3H,m), 7.60-7.70 (2H, m), 8.04 (0.5H, d, J=1.1 Hz), 8.10 (0.5H, d, J=1.1Hz), 8.32 (1H, s), 11.46 (1H, br).

EXAMPLE 250

(2E)-3-(6-{[(3R)-1-(2,2-difluoroethyl)-3-pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 331 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.60 (2H, m), 3.05-4.10 (4H, m),3.87 (2H, dt, J=3.8 Hz, J=13 Hz), 4.50-4.90 (1H, m), 6.33 (1H, d, J=16Hz), 6.57 (1H, tt, J=3.8 Hz, J=54 Hz), 7.39 (1H, d, J=16 Hz), 7.60 (1H,br), 7.69 (1H, d, J=13 Hz), 8.08 (1H, s).

EXAMPLE 0.251

(2E)-3-[5-fluoro-6-({(3R)-1-[2-(1H-pyrazol-1-yl)ethyl]-3-pyrrolidinyl}amino)-3-pyridinyl]-N-hydroxyacrylamidedihydrochloride

MASS(API-ES); 361 (M+H)+Free,

¹H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.85-3.90 (6H, m),4.60 (2H, t, J=6.4 Hz), 4.65 (1H, br), 6.25-6.40 (2H, m), 7.38 (1H, d,J=16 Hz), 7.54 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=13 Hz), 7.85 (1H, d,J=2.2 Hz), 8.06 (1H, s), 11.20-11.60 (1H, m).

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 252

(2E)-3-(5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}-3-pyridinyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.26 (1H, m), 1.41 (1H, m), 2.12 (1H, m),3.02 (1H, m), 6.34 (1H, d, J=16 Hz), 7.13-7.22 (3H, m), 7.24-7.38 (3H,m), 7.51 (1H, br), 7.92 (1H, s), 8.21 (1H, s); MS (ES−) m/z 328.

The following compound was obtained in a similar manner to that ofExample 41.

EXAMPLE 253

(2E)-3-(5-chloro-6-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.05-1.70 (6H, m), 1.77-1.82 (2H, m),2.05-2.09 (3H, m), 3.00-3.78 (5H, m), 4.72-4.86 (1H, m), 5.75 (1H, d,J=15.8 Hz), 7.20 (1H, brs), 7.35 (1H, d, J=15.8 Hz), 7.91 (1H, s), 8.22(1H, s), 11.32 (1H, brs).

The following compound was obtained in a similar manner to that ofExample 89.

EXAMPLE 254

tert-butyl(3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

¹H-NMR (200 MHz, DMSO-d6) δ: 1.39 (9H, s), 1.91-2.12 (2H, m), 3.15-3.65(4H, m), 4.53 (1H, brs), 6.33 (1H, d, J=15.8 Hz), 6.85 (1H, brs), 7.34(1H, d, J=15.8 Hz), 7.88 (1H, s), 8.22 (1H, s).

MASS(ESI); 383 (M+H)+.

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 255

(2E)-3-(5-chloro-6-{[1-(3-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 2.00-2.20 (4H, m), 3.00-3.46 (4H, m), 4.10-4.20(1H, m), 4.30-4.46 (2H, m), 6.39 (1H, d, J=15.9 Hz), 7.26-7.58 (4H, m),7.66 (1H, d, J=8.3 Hz), 7.95 (1H, s), 8.18-8.22 (1H, m),

Mass (APCI): 405(M+H)+.

EXAMPLE 256

(2E)-3-(5-chloro-6-{[1-(2-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidetrihydrochloride

¹H NMR (DMSO-d6, δ): 2.05-2.10(4H, m), 3.17-3.25(2H, m), 3.41-4.78(2H,m), 4.15-4.25(1H, m), 4.51(2H, s), 6.37(1H, d, J=15.8 Hz), 7.04(1H,brs), 7.34(1H, d, J=15.8 Hz), 7.56-7.59(1H, m), 7.83(1H, d, J=7.8 Hz),7.93(1H, s), 8.02-8.06(1H, d), 8.19(1H, s), 8.73(1H, d, J=4.9 Hz),10.97(1H, brs),

Mass (APCI): 388(M+H)+.

EXAMPLE 257

(2E)-3-(5-chloro-6-{[1-(3-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidetrihydrochloride

¹H NMR (DMSO-d6, δ): 2.00-2.30(4H, m), 3.05-3.45(2H, m), 3.45-3.50(2H,m), 4.15-4.35(1H, m), 4.57(2H, brs), 6.39(1H, d, J=15.9 Hz), 7.23(1H,brs), 7.34(1H, d, J=15.9 Hz), 7.94(1H, s), 8.09-8.16(1H, m), 8.18(1H,s), 8.89(1H, d, J=7.9 Hz), 9.00(1H, d, J=5.4 Hz), 9.24(1H, s), 11.80(1H,brs),

Mass (ESI): 388(M+H)+.

EXAMPLE 258

(2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidetrihydrochloride

¹H NMR (DMSO-d6, δ): 2.00-2.30(4H, m), 3.10-3.60(4H, m), 4.10-4.30(1H,m), 4.62(2H, brs), 6.37(1H, d, J=15.9 Hz), 7.17(1H, brs), 7.34(1H, d,J=15.9 Hz), 7.92(1H, s), 8.18(1H, s), 8.42(2H, m), 9.04(2H, d, J=5.8Hz), 12.06(1H, brs),

Mass (ESI): 388(M+H)+.

EXAMPLE 259

(2E)-3-(5-chloro-6-{[1-(3-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 2.00-2.25(4H, m), 2.90-3.20(2H, m), 3.20-3.40(2H,m), 4.10-4.30(1H, m), 4.29-4.44(2H, m), 6.38(1H, d, J=15.9 Hz), 7.35(1H,d, J=15.9 Hz), 7.49-7.67(3H, m), 7.84(1H, s), 8.04(1H, s), 8.19(1H, s),11.30(1H, brs),

Mass (ESI): 421(M+H)+.

EXAMPLE 260

(2E)-3-(5-chloro-6-{[1-(2-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 2.00-2.25(4H, m), 3.10-3.50(4H, m), 4.10-4.30(1H,m), 4.42-4.56(2H, m), 6.38(1H, d, J=15.9 Hz), 7.35(1H, d, J=15.9 Hz),7.46-7.62(3H, m), 7.93(1H, s), 8.04-8.09(1H, m), 8.19(1H, s), 11.20(1H,brs),

Mass (ESI): 421(M+H)+.

EXAMPLE 261

(2E)-3-(5-chloro-6-{[1-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 0.94-1.29 (7H, m), 1.65-1.92 (5H, m), 1.99-2.17(3H, m), 2.86-3.04 (3H, m), 3.10-3.54 (3H, m), 4.19-4.31 (1H, m), 6.40(1H, d, J=15.9 Hz), 7.35 (1H, d, J=15.9 Hz), 8.20 (1H, s), 8.30 (1H, s),10.30 (1H, brs),

Mass (APCI): 393(M+H)+.

EXAMPLE 262

(2E)-3-(5-chloro-6-{[1-(2-fluorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 2.05-2.20(4H, m), 3.08-3.18(2H, m), 3.41-3.44(2H,m), 4.15-4.20(1H, m), 4.32-4.46(2H, m), 6.38(1H, d, J=15.9 Hz),7.30-7.37(3H, m), 7.52-7.56(1H, m), 7.86-7.89(1H, m), 7.93(1H, s),8.19(1H, s), 11.22(1H, brs),

Mass (APCI): 405(M+H)+.

EXAMPLE 263

(2E)-3-(5-chloro-6-{[1-(3-methyl-2-buten-1-yl)-4-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H NMR (DMSO-d6, δ): 1.72 (3H, s), 1.78 (3H, s), 2.90-3.30 (2H, m),3.30-3.50 (2H, m), 3.55-3.80 (2H, m), 4.10-4.40 (1H, m), 5.37-5.44 (1H,m), 6.39 (1H, d, J=15.9 Hz), 7.35 (1H, d, J=15.9 Hz), 7.94 (1H, s), 8.19(1H, s),

Mass (APCI): 365(M+H)+.

The following compounds were obtained in a similar manner to that ofExample 129.

EXAMPLE 264

(2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide

¹H-NMR (300 MHz, DMSO-d6) δ 1.10-1.40 (5H, m), 1.54-1.95 (6H, m),2.02-2.45 (2H, m), 3.25-4.15 (5H, m), 6.15 (1H, br-d, J=16 Hz), 6.34(1H, m), 6.56-6.70 (2H, m), 7.26-7.40 (3H, m), 8.86 (1H, s), 10.53 (1H,s);

MS (ES+) m/z 358.

EXAMPLE 265

(2E)-N-hydroxy-3-{6-[(4-methylphenyl)amino]-3-pyridinyl}acrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 2.31 (3H, s), 6.38 (1H, d, J=16 Hz), 7.06(1H, d, J=9 Hz), 7.22 (2H, d, J=8 Hz), 7.38-7.50 (3H, m), 8.00 (1H,br-d, J=8 Hz), 8.23 (1H, d, J=1.5 Hz), 10.27 (1H, br-s); MS (ES+) m/z270.

EXAMPLE 266

(2E)-3-{6-[(2-ethoxyphenyl)amino]-3-pyridinyl}-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.21 (3H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz),6.44 (1H, d, J=15.8 Hz), 7.03 (1H, dd, J=7.5, 7.5 Hz), 7.17 (1H, d, J=8Hz), 7.21 (1H, d, J=9.5 Hz), 7.30 (1H, dd, J=7.5, 7.5 Hz), 7.46 (1H, d,3=15.8 Hz), 7.53 (1H, br-d, J=7.5 Hz), 8.13 (1H, br-d, J=9.5 Hz), 8.21(1H, d, J=1.5 Hz), 10.38 (1H, br), 10.82 (1H, br); MS (ES+) m/z 300.

EXAMPLE 267

(2E)-3-[5-chloro-6-(2,3-dihydro-1H-inden-1-ylamino)-3-pyridinyl]-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6)δ 2.09 (1H, m), 2.77-3.06 (3H, m), 5.78 (1H,m), 6.35 (1H, d, J=16 Hz), 7.12-7.32 (5H, m), 7.37 (1H, d, J=16 Hz),7.94 (1H, s), 8.24 (1H, s); MS (ES+) m/z 330.

The following compound was obtained in a similar manner to that ofExample 96.

EXAMPLE 268

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.39-1.49 (1H, m), 1.70-2.06 (3H, m),2.70-2.94 (1H, m), 2.94-3.21 (1H, m), 3.30-3.61 (2H, m), 4.21-4.41 (1H,m), 4.41-4.56 (2H, m), 6.62 (1H, d, J=15.2 Hz), 7.37 (1H, d, J=15.2 Hz),7.44-7.55 (2H, m), 7.55-7.65 (1H, m), 7.72-7.87 (1H, m), 7.87-7.99 (1H,m), 7.99-8.06 (1H, m), 8.11 (1H, s); MS (ES+) m/z 388.

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 269

(2E)-3-(4-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamidehydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 0.84-1.03 (2H, m), 1.08-1.32 (3H, m),1.54-1.76 (4H, m), 1.79-2.02 (3H, m), 2.22-2.50 (1H, m), 2.82-3.14 (3H,m), 3.40 (1H, m), 3.60 (1H, m), 3.87-4.40 (2H, m), 6.20 (1H, d, J=16Hz), 6.62 (2H, d, J=8 Hz), 7.26-7.42 (3H, m), 10.46 (1H, s); MS (ES+)m/z 344.

The following compounds were obtained in a similar manner to that ofExample 41.

EXAMPLE 270

(2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.30-1.60 (1H, m), 1.70-1.98 (3H, m),2.60-2.90 (2H, m), 3.25-3.50 (3H, m), 4.35 (2H, m), 6.34 (1H, d, J=16.1Hz), 7.37 (1H, d, J=16.1 Hz), 7.41-7.47 (4H, m), 7.61-7.75 (3H, m), 8.03(1H, s), 11.20 (1H, brs),

MASS(ESI); 371 (M+H)+.

EXAMPLE 271

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 0.92-1.27 (5H, m), 1.52-2.02 (10H, m),2.73-3.00 (3H, m), 3.20-3.57 (2H, m), 4.55-4.60 (2H, m), 6.34 (1H, d,J=16.1 Hz), 7.34-7.43 (2H, m), 7.64-7.76 (1H, m), 8.67 (1H, s), 10.11(1H, brs),

MASS(ESI); 377 (M+H)+.

EXAMPLE 272

(2E)-3-(2-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-pyrimidinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 1.35-1.60 (1H, m), 1.70-2.00 (4H, m),2.61-3.10 (2H, m), 3.20-3.67 (2H, m), 4.34 (2H, m), 6.39 (1H, d, J=16.0Hz), 7.20 (1H, d, J=16.0 Hz), 7.44-7.47 (3H, m), 7.59-7.64 (2H, m), 8.15(1H, d, J=8.0 Hz), 8.55 (2H, s), 11.07 (1H, brs),

MASS(ESI); 354 (M+H)+.

EXAMPLE 273

(2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-5-pyrimidinyl)-N-hydroxyacrylamidedihydrochloride

¹H-NMR (200 MHz, DMSO-d6) δ: 0.92-1.28 (5H, m), 1.64-2.10 (10H, m),2.70-3.16 (3H, m), 3.32-3.57 (2H, m), 4.44 (2H, brs), 6.47 (1H, d,J=16.0 Hz), 7.33 (1H, d, J=16.0 Hz), 8.03 (1H, brs), 8.62 (2H, s), 10.40(1H, brs),

MASS(ESI); 360 (M+H)+.

The following compound was obtained in a similar manner to that ofExample 129.

EXAMPLE 274

(2E)-3-(5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}-3′pyridinyl)-N-hydroxyacrylamide dihydrochloride

¹H-NMR (300 MHz, DMSO-d6) δ 1.76-2.00 (4H, m), 2.96-3.13 (2H, m),3.27-3.42 (2H, m), 4.23 (2H, br-s), 6.38 (1H, d, J=16 Hz), 7.30-7.52(4H, m), 7.78 (1H, d, J=7.5 Hz), 8.02 (1H, s), 8.10 (1H, s), 8.81 (1H,s), 10.96 (1H, br-s); MS (ES+) m/z 373.

EXAMPLE 275

1N-NaOH (4.7 mL) was added to the solution of(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamidedihydrochloride (1.0 g) in water (20 mL) under ice-cooling and themixture was stirred at 5-10 deg for 5 hr. The isolated precipitate wascollected by filtration to give(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide(0.71 g).

¹H-NMR(CD₃OD):d 1.77-1.89(1H, m), 2.33-2.46(1H, m), 2.71-2.91(6H, m),2.94-3.04(1H, m), 3.10-3.17(1H, m), 4.43-4.52(1H, m), 6.64(1H, d, J=15.3Hz), 7.16-7.32(5H, m), 7.45(1H, d, J=15.3 Hz), 7.95(1H, s), 8.01(1H, s)

The following compounds can be obtained in a similar manner to that ofExample 275.

EXAMPLE 276

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

EXAMPLE 277

(2E)-3-(6-{[(3R)-1-(1-benzofuran-2-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

EXAMPLE 278

(2E)-3-(6-{[(3R)-1-(1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

EXAMPLE 279

(2E)-3-(6-{[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

EXAMPLE 280

(2E)-3-(6-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

EXAMPLE 281

(2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide

EXAMPLE 282

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide

EXAMPLE 283

tert-butyl(3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

EXAMPLE 284

(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide

EXAMPLE 285

cyclopentyl(3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

EXAMPLE 286

(2E)-N-hydroxy-3-(5-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide

EXAMPLE 287

(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide

EXAMPLE 288

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide

EXAMPLE 289

(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide

EXAMPLE 290

A solution of acetic acid (3.2 μL) in acetonitrile (29.2 μL) was addedto the mixture of(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide(20 mg) in THF (0.1 mL) and acetonitrile (0.1 mL) and the mixture wasstirred at ambient temperature for 5 minutes. To the mixture was addedAcOEt (1.5 mL) and isolated precipitate was collected by filtration togive(2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamideacetate (18 mg).

¹H-NMR(DMSO-d6):d 1.59-1.70(1H, m), 1.91(3H, s), 2.15-2.27(1H, m),2.43-2.53(2H, m), 2.60-2.66(2H, m), 2.70-2.77(3H, m), 2.79-2.85(1H, m),4.26-4.36(1H, m), 6.58(1H, d, J=15.2 Hz), 7.15-7.31(5H, m), 7.37(1H, d,J=15.2 Hz), 7.73(1H, d, J=6.6 Hz), 7.98(1H, s), 8.10(1H, s), 10.71(1H,br-s)

The following compounds can be obtained in a similar manner to that ofExample 290.

EXAMPLE 291

(2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamideacetate

EXAMPLE 292

(2E)-3-(6-{[(3R)-1-(1-benzofuran-2-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamideacetate

EXAMPLE 293

(2E)-3-(6-{[(3R)-1-(1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamideacetate

EXAMPLE 294

(2E)-3-(6-{[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamideacetate

EXAMPLE 295

(2E)-3-(6-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamideacetate

EXAMPLE 296

(2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamideacetate

EXAMPLE 297

(2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamideacetate

EXAMPLE 298

tert-butyl(3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylateacetate

EXAMPLE 299

(2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamideacetate

EXAMPLE 300

cyclopentyl(3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylateacetate

EXAMPLE 301

(2E)-N-hydroxy-3-(5-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamideacetate

EXAMPLE 302

(2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamideacetate

EXAMPLE 303

(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamideacetate

EXAMPLE 304

(2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamideacetate

1. A compound having the following formula (I):

wherein R¹ is hydrogen, lower alkyl, lower alkenyl, lower or higheralkynyl, cyclo(lower)alkyl, cyclo(higher)alkyl,cyclo(lower)alkyl(lower)alkyl, cyclo(higher)alkyl(lower)alkyl,cyclo(lower)alkenyl(lower)alkyl, aryl-fused cyclo(lower)alkyl, loweralkoxy, acyl, aryl, ar(lower)alkoxy, ar(lower) alkyl,heteroar(lower)alkyl, amino, heteroaryl, heterocyclyl orheterocyclyl(lower)alkyl, which may be substituted with one or moresuitable substituent(s), R² is hydrogen or lower alkyl, X is arylene,heteroarylene, cycloalkylene, heterocycloalkylene or aryl-fusedcycloalkylene, Y is arylene or heteroarylene, which may be substitutedwith one or more suitable substituent(s), Z is lower alkenylene, whichmay be substituted with lower alkyl or halogen, or a salt thereof. 2.The compound of claim 1, wherein R¹ is hydrogen, lower alkyl, loweralkenyl, lower or higher alkynyl, cyclo(lower)alkyl, cyclo(higher)alkyl,cyclo(lower)alkyl(lower)alkyl, cyclo(higher)alkyl(lower)alkyl,cyclo(lower)alkenyl(lower)alkyl, aryl-fused cyclo(lower)alkyl, loweralkoxy, acyl, aryl, ar(lower)alkoxy, ar(lower)alkyl,heteroar(lower)alkyl, amino, heteroaryl, heterocyclyl orheterocyclyl(lower)alkyl, which may be substituted with one or moresuitable substituent(s) selected from the group consisting of loweralkyl, halogen, lower alkoxy, amino, hydroxy, cyano, aryl, aryloxy,acyl, cyclo(lower)alkyl, heteroaryl, halo(lower)alkyl orhalo(lower)alkoxy, Y is aryl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl or thiazolyl, which may be substituted with one or moresuitable substituent(s) selected from the group consisting of halogen orlower alkyl Z is vinylene, which may be substituted with lower alkyl orhalogen, or a salt thereof.
 3. The compound of claim 2, wherein R¹ islower alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, acyl,aryl, ar(lower)alkyl, heteroar(lower)alkyl, heteroaryl or heterocyclyl,which may be substituted with one or more suitable substituent(s)selected from the group consisting of lower alkyl, halogen, loweralkoxy, amino, hydroxy, cyano, aryl, aryloxy, acyl, cyclo(lower)alkyl,heteroaryl, halo(lower)alkyl or halo(lower)alkoxy, R² is hydrogen, Z isvinylene, which may be substituted with methyl or fluorine, or a saltthereof.
 4. The compound of claim 3, wherein X is pyrrolidinyl orpiperidinyl, or a salt thereof.
 5. The compound of claim 4, wherein R¹is ar(lower)alkyl or heteroar(lower)alkyl optionally substituted withlower alkyl, halogen, lower alkoxy, amino, hydroxy, cyano, aryl,aryloxy, acyl, cyclo(lower)alkyl, heteroaryl, halo(lower)alkyl orhalo(lower)alkoxy, or a salt thereof.
 6. The compound of claim 5,wherein R¹ is ar(lower)alkyl or heteroar(lower)alkyl optionallysubstituted with lower alkyl, halogen, lower alkoxy,di(lower)alkylamino, lower alkanoylamino, lower alkylsulfonylamino,hydroxy, cyano, arylcarbonyl, cyclo(lower)alkyl, halo(lower)alkyl orhalo(lower)alkoxy, Z is vinylene, or a salt thereof.
 7. The compound ofclaim 6, wherein Y is pyrazinyl, or a salt thereof.
 8. A histonedeacetylase inhibitor comprising the compound of claim
 1. 9. Apharmaceutical composition for treating or preventing inflammatorydisorders, diabetes, diabetic complications, homozygous thalassemia,fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organtransplant rejections, autoimmune diseases, protozoal infections ortumors, which comprises the compound of claim
 1. 10. A pharmaceuticalcomposition containing the compound of claim 1 as an active ingredient,in association with a pharmaceutically acceptable, substantiallynon-toxic carrier or excipient.
 11. The compound of claim 1 for use as amedicament.
 12. A method for inhibiting histone deacetylase, comprisingusing the compound of claim
 1. 13. Use of the compound of claim 1 forthe manufacture of a medicament for inhibiting hostone deacetylase. 14.A method for treating or preventing inflammatory disorders, diabetes,diabetic complications, homozygous thalassemia, fibrosis, cirrhosis,acute promyelocytic leukaemia (APL), organ transplant rejections,autoimmune diseases, protozoal infections or tumors, which comprisesadministering an effective amount of the compound of claim 1 to a humanbeing or an animal.
 15. Use of the compound of claim 1 for themanufacture of a medicament for treating or preventing inflammatroydisorders, diabetes, diabetic complications, homozygous thalassemia,fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organtransplant rejections, autoimmune diseases, protozoal infections ortumors.
 16. A commercial package comprising the pharmaceuticalcomposition of claim 3 and a written matter associated therewith, thewritten matter stating that the pharmaceutical composition may or shouldbe used for treating or preventing inflammatory disorders, diabetes,diabetic complications, homozygous thalassemia, fibrosis, cirrhosis,acute promyelocytic leukaemia (APL), organ transplant rejections,autoimmune diseases, protozoal infections or tumors.